Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Colonic Potassium Absorption and Secretion in Health and Disease

Vazhaikkurichi M. Rajendran, Geoffrey I. Sandle

10.1002/cphy.c170030

Source: Volume 8, Issue 4, October 2018

Published online: September 2018

Full Article on Wiley Online Library



ABSTRACT

The colon has large capacities for K+ absorption and K+ secretion, but its role in maintaining K+ homeostasis is often overlooked. For many years, passive diffusion and/or solvent drag were thought to be the primary mechanisms for K+ absorption in human and animal colon. However, it is now clear that apical H+,K+‐ATPase, in coordination with basolateral K+‐Cl− cotransport and/or K+ and Cl− channels operating in parallel, mediate electroneutral K+ absorption in animal colon. We now know that K+ absorption in rat colon reflects ouabain‐sensitive and ouabain‐insensitive apical H+,K+‐ATPase activities. Ouabain‐insensitive and ouabain‐sensitive H+,K+‐ATPases are localized in surface and crypt cells, respectively. Colonic H+,K+‐ATPase consists of α‐ (HKCα) and β‐ (HKCβ) subunits which, when coexpressed, exhibit ouabain‐insensitive H+,K+‐ATPase activity in HEK293 cells, while HKCα coexpressed with the gastric β‐subunit exhibits ouabain‐sensitive H+,K+‐ATPase activity in Xenopus oocytes. Aldosterone enhances apical H+,K+‐ATPase activity, HKCα specific mRNA and protein expression, and K+ absorption. Active K+ secretion, on the other hand, is mediated by apical K+ channels operating in a coordinated way with the basolateral Na+‐K+‐2Cl− cotransporter. Both Ca2+‐activated intermediate conductance K+ (IK) and large conductance K+ (BK) channels are located in the apical membrane of colonic epithelia. IK channel‐mediated K+ efflux provides the driving force for Cl− secretion, while BK channels mediate active (e.g., cAMP‐activated) K+ secretion. BK channel expression and activity are increased in patients with end‐stage renal disease and ulcerative colitis. This review summarizes the role of apical H+,K+‐ATPase in K+ absorption, and apical BK channel function in K+ secretion in health and disease. © 2018 American Physiological Society. Compr Physiol 8:1513‐1536, 2018.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Role of normal human small intestine and colon in K+ absorption and K+ secretion. Normal dietary K+ intake is approximately 90 mEq/day. Salivary, gastric, pancreatic, and intestinal secretions also contribute to the intestinal K+ content. Thus, approximately 83 mEq K+/day (i.e., 90%) is absorbed in the small intestine, and only 10 mEq K+/day (i.e., ∼10%) enters the colon. The colon secretes and absorbs 5 mEq K+/day, and thus fecal K+ excretion is 10 mEq/day. Small intestinal K+ absorption occurs secondary to passive driving forces, such as solvent drag and/or membrane electrical potential. Proximal colon secretes K+, while K+ absorption occurs in distal colon. Average lumen‐negative electrical potentials are −1, −8, −12, and −31 mV in the jejunum, ileum, proximal colon, and distal colon, respectively (42). Outward and inward arrows indicate K+ absorption and K+ secretion, respectively. Thickness of arrows represent relative rate of absorption and secretion.
Figure 2. Figure 2. Cellular models of electroneutral K+ absorption in animal (guinea pig, mouse, and rat) distal colon. Apical H+,K+‐ATPase, and either basolateral parallel exit of K+ and Cl− through respective channels (A) or K+‐Cl− cotransport (KCC) (B), mediate electroneutral K+ absorption in animal colon. H+,K+‐ATPase‐mediated K+ absorption is partially Cl−‐dependent. It is not known whether anion exchanger (AE)‐mediated Cl−‐HCO3− exchange plays a role in Cl−‐dependent K+ absorption.
Figure 3. Figure 3. Distribution of ouabain‐insensitive and ouabain‐sensitive H+,K+‐ATPase along the surface to crypt cell axis in rat distal colon. Ouabain‐insensitive H+,K+‐ATPase is localized in surface cells and upper one‐third of matured crypt cells (yellow‐colored cells), while ouabain‐insensitive H+,K+‐ATPase is localized mainly to crypt cells (red‐colored cells). Vanadate (VO4, H+,K+‐ATPase inhibitor) inhibits both ouabain‐insensitive and ouabain‐sensitive H+,K+‐ATPase.
Figure 4. Figure 4. Effect of Na+‐free diet (aldosterone) on active K+ absorption and active K+ secretion in rat colon. Active K+ secretion and active K+ absorption are present in proximal (lined segment) and distal segments of normal rat colon, respectively. Active K+ absorption is mediated by H+,K+‐ATPase, while active K+ secretion is mediated via large conductance K+ (BK) channels. Dietary Na+ depletion induces active K+ secretion in distal colon. Dietary Na+ depletion also stimulates H+,K+‐ATPase‐mediated active K+ absorption in distal colon. Dietary Na+ depletion enhances BK channel and H+,K+‐ATPase‐specific protein expression in distal colon. It is not known whether dietary Na+ depletion also stimulates active K+ secretion in proximal colon.
Figure 5. Figure 5. Cellular model of active K+ secretion. Coordinated activation of apical large conductance K+ (BK) channels, and basolateral Na+‐K+‐2Cl− cotransporter (NKCC) and Cl− channel 2 (ClC2) regulates active K+ secretion. K+ entering cells via basolateral NKCC (K+ loader) exits via apical BK channels. K+ entering via Na+,K+‐ATPase also contributes to apical BK channel‐mediated K+ secretion. Continuous K+ secretion depends on CLC2 and Na+,K+‐ATPase maintaining low intracellular levels of Cl− and Na+, respectively. cAMP activates both basolateral NKCC and apical BK channel. Mucosal iberiotoxin IbTX inhibits active K+ secretion. [Reproduced, with permission, from (159).]
Figure 6. Figure 6. Colonic epithelial cell models for basolateral membrane K+ channel‐regulated transport processes. (A) Under basal conditions, K+ recycling across basolateral membranes via intermediate conductance K+ (IK) channels operating in concert with Na+,K+‐ATPase, contributes to the favorable electrochemical gradient (reflecting high intracellular K+ and low intracellular Na+ concentrations, and a negative membrane potential) necessary for the secondary Na+ absorption mediated by apical Na+‐H+ exchanger isoforms 2 and 3 (NHE2/NHE3) and epithelial Na+ channel (ENaC). NHE2 and NHE3 mediate electroneutral Na+ absorption, while ENaC mediates electrogenic Na+ absorption. (B) Under stimulated condition (e.g., cholera), apical Cl− exit via CFTR (cystic fibrosis transmembrane regulator) Cl− channels following Na+‐K+‐2Cl− (NKCC) transporter‐mediated basolateral Cl− uptake tends to depolarize cells. This is counter‐balanced by the hyperpolarizing effect of K+ exit through basolateral IK channels, thus maintaining the electrical gradient required for sustained Cl− secretion.
Figure 7. Figure 7. Effect of cellular cAMP increased by serosal addition of forskolin (FSK, adenylate cyclase activator) on K+ fluxes in the presence and absence of mucosal VO4 (P‐type ATPase inhibitor) in rat distal colon. (A) In the absence of mucosal VO4, FSK significantly inhibits active K+ absorption (i.e., net K+ absorption) by stimulating s‐m K+ fluxes. (B) Presence of 1 mmol/L mucosal VO4 unmasks FKS‐induced active K+ secretion. It is to be noted that mucosal VO4 also inhibits basal K+ absorption in normal colon (see Fig. 11). Mucosal to serosal (m‐s) and serosal to mucosal (s‐m) 86Rb+ fluxes (K+ surrogate) were measured under voltage clamp condition in the absence (green bars) and presence (red bars) of forskolin. Net K+ fluxes were calculated by subtracting s‐m fluxes from m‐s fluxes. Positive and negative fluxes represent active K+ absorption and active K+ secretion, respectively. *P < 0.001—compared to respective fluxes in the absence of FSK; £P < 0.05—compared to in the absence of FSK. [Reproduced, with permission, from ref. (159).]
Figure 8. Figure 8. Immunogold labeling of intermediate conductance K+ (IK) channels in colonic surface epithelial cells of normal rat distal colon (RtDC) and normal human colon (HuC). Cryosemithin sections were prepared and trypan blue‐stained for orientation (left column of each panel). Tissue specimens were ultratrimmed for cryothin sectioning, focusing on small areas of interest in the colonic surface epithelium to characterize plasma membrane domain‐specific localization of IK channel proteins at the ultrastructural level. Cryothin sections were immunolabeled with anti‐IKabc and detected with a secondary donkey anti‐rabbit 10 nm gold‐labeled antibody. Anti‐IKabc localized IK‐like proteins in apical [A], and lateral [L] plasma membrane domains of rat and human colonic epithelial cells, but not in basal plasma membranes [B] of surface epithelial enterocytes. These results using high‐resolution immunogold electron microscopy confirm our earlier results using confocal microscopy. [S] Surface epithelium; [C] crypts; [n] nucleus; [bm] basal plasma membrane. Images were acquired either at 400× primary magnification (cryosemithin section, bar = 20 µm) by light microscopy, or at 21,000× primary magnification (cryothin sections, bar = 200 nm) by electron microscopy. Similar results were obtained with two and three different human and rat tissues, respectively. [Reproduced, with permission, from ref. (12).]
Figure 9. Figure 9. Indirect immunofluorescence imaging of intermediate conductance K+ (IK) channel protein in cRNA‐injected Xenopus oocytes. Anti‐IKabc antibody localized IK channel proteins to the plasma membrane of IKb cRNA‐injected oocytes (IKb), but not water injected (control) oocytes. IK protein was identified only in the cytoplasm, but not in the plasm membrane of IKc cRNA‐injected oocytes (IKc). Plasma membrane targeting of IK protein was substantially enhanced in oocytes coinjected with IKc and the BKβ1 subunit (i.e., large conductance K+ channel β‐subunit) cRNAs (IKc + BKβ1). Arrowheads indicate the absence (or minimal presence) of IK cahnnel proteins (left panels), while arrows indicate the presence of IK channel proteins (right panels) on the plasma membrane of oocytes. Fluorescence images were acquired using Nikon light microscope. Bar = 0.1 mm. [Adapted, with permission, from ref. (12).]
Figure 10. Figure 10. Mucosal DC‐EBIO [intermediate conductance K+ (IK) channel opener] activates IK channel mediated K+ secretion in normal rat distal colon. Minimal K+ secretion is present under basal conditions. Mucosal DC‐EBIO stimulates active K+ secretion. Mucosal TRAM‐34 (IK channel blocker) inhibits DC‐EBIO‐stimulated K+ secretion. DC‐EBIO‐stimulated K+ secretion is not inhibited by mucosal iberiotoxin IbTX, large conductance K+ (BK) channel blocker). [Reproduced, with permission, from ref. (124).]
Figure 11. Figure 11. Active K+ transport in normal and aldosterone‐treated (dietary Na+ depleted) rat distal colon. Net K+ transport was determined from the difference between mucosal to serosal (m‐s) and serosal to mucosal (s‐m) unidirectional fluxes measured under voltage clamp conditions. Net positive value represent active K+ absorption, while net negative value represent active K+ secretion. (A) Active K+ absorption present in normal rat distal colon (green bars) was inhibited by mucosal vanadate (VO4; P‐type ATPase inhibitor; red bars). (B) Active K+ secretion in aldosterone‐treated rat distal colon was further stimulated by mucosal VO4. *P < 0.001—compared to control; £P < 0.001—compared to control; ‡P < 0.001—compared to control. [Reproduced, with permission, from ref. (176).]
Figure 12. Figure 12. Effect of actinomycin D on aldosterone‐induced Isc in normal rat distal colon in vitro. (A) Normal rat distal colonic mucosal layers were mounted under voltage clamp condition in Ussing chambers. Immediately after mounting, either aldosterone (aldo) or aldosterone plus actinomycin D (transcriptional inhibitor) (aldo/act‐D) was added to the serosal bath. Short circuit current (Isc) was measured for up to 9 h. At the end of 8½ h, 10 µmol/L amiloride was added to mucosal bath. Enhanced Isc and inhbition of Isc by amiloride indicates that aldosterone induced epithelial Na+ channel (ENaC)‐mediated Na+ absorption (aldo). Absence of amiloride‐sensitive Isc in the presence of actinomycin D (aldo/act‐D) indicates that aldosterone‐induced ENaC‐mediated Na+ absorption is regulated at transcriptional level. (B) RT‐qPCR analyses indicated that aldosterone enhanced the abundance of large conductance K+ channel α‐subunit (BKα)‐specific mRNA (aldo), while this change was prevented by actinomycin D (aldo/act‐D). (C) K+ fluxes measured under voltage clamp condition indicate that aldosterone stimulated active K+ secretion (aldo), whereas this response was blocked by actinomycin D (aldo/act‐D). [Reproduced, with permission, from ref. (176).]
Figure 13. Figure 13. Dextran sulfate sodium (DSS)‐induced inflammation stimulates active K+ secretion and abolishes agonist (cAMP and Ca2+)‐stimulated Cl− secretion in rat distal colon. (A) Positive Isc (short circuit current) represents the presence of anion (Cl−/HCO3−) secretion under basal conditions. Increasing intracellular cAMP by forskolin (FSK; adenylate cyclase activator) stimulated active Cl− secretion. Increasing intracellular Ca2+ by carbachol (CCH; adrenergic agonist; FSK/CCH) further transiently stimulated active Cl− secretion. (B) Negative Isc indicates induced cation secretion and absence of anion secretion under basal conditions in DSS‐inflamed colon. The minimal increase in Isc induced by FSK, and the absence of a FSK/CCH‐induced Isc, indicated that Cl− secretory processes were abolished in DSS‐inflamed colon. (C) In the presence of mucosal ortho‐VO4 (H+,K+‐ATPase inhibitor), minimal K+ absorption was present in normal colon (control). In normal colon, FSK stimulated active K+ secretion, while FSK/CCH had no additional effect on K+ secretion. (D) In DSS‐inflamed colon (control), active K+ secretion was present under basal conditions, but neither FSK nor FSK/CCH stimulated active K+ secretion. [Reproduced, with permission, from ref. (94).]


Figure 1. Role of normal human small intestine and colon in K+ absorption and K+ secretion. Normal dietary K+ intake is approximately 90 mEq/day. Salivary, gastric, pancreatic, and intestinal secretions also contribute to the intestinal K+ content. Thus, approximately 83 mEq K+/day (i.e., 90%) is absorbed in the small intestine, and only 10 mEq K+/day (i.e., ∼10%) enters the colon. The colon secretes and absorbs 5 mEq K+/day, and thus fecal K+ excretion is 10 mEq/day. Small intestinal K+ absorption occurs secondary to passive driving forces, such as solvent drag and/or membrane electrical potential. Proximal colon secretes K+, while K+ absorption occurs in distal colon. Average lumen‐negative electrical potentials are −1, −8, −12, and −31 mV in the jejunum, ileum, proximal colon, and distal colon, respectively (42). Outward and inward arrows indicate K+ absorption and K+ secretion, respectively. Thickness of arrows represent relative rate of absorption and secretion.


Figure 2. Cellular models of electroneutral K+ absorption in animal (guinea pig, mouse, and rat) distal colon. Apical H+,K+‐ATPase, and either basolateral parallel exit of K+ and Cl− through respective channels (A) or K+‐Cl− cotransport (KCC) (B), mediate electroneutral K+ absorption in animal colon. H+,K+‐ATPase‐mediated K+ absorption is partially Cl−‐dependent. It is not known whether anion exchanger (AE)‐mediated Cl−‐HCO3− exchange plays a role in Cl−‐dependent K+ absorption.


Figure 3. Distribution of ouabain‐insensitive and ouabain‐sensitive H+,K+‐ATPase along the surface to crypt cell axis in rat distal colon. Ouabain‐insensitive H+,K+‐ATPase is localized in surface cells and upper one‐third of matured crypt cells (yellow‐colored cells), while ouabain‐insensitive H+,K+‐ATPase is localized mainly to crypt cells (red‐colored cells). Vanadate (VO4, H+,K+‐ATPase inhibitor) inhibits both ouabain‐insensitive and ouabain‐sensitive H+,K+‐ATPase.


Figure 4. Effect of Na+‐free diet (aldosterone) on active K+ absorption and active K+ secretion in rat colon. Active K+ secretion and active K+ absorption are present in proximal (lined segment) and distal segments of normal rat colon, respectively. Active K+ absorption is mediated by H+,K+‐ATPase, while active K+ secretion is mediated via large conductance K+ (BK) channels. Dietary Na+ depletion induces active K+ secretion in distal colon. Dietary Na+ depletion also stimulates H+,K+‐ATPase‐mediated active K+ absorption in distal colon. Dietary Na+ depletion enhances BK channel and H+,K+‐ATPase‐specific protein expression in distal colon. It is not known whether dietary Na+ depletion also stimulates active K+ secretion in proximal colon.


Figure 5. Cellular model of active K+ secretion. Coordinated activation of apical large conductance K+ (BK) channels, and basolateral Na+‐K+‐2Cl− cotransporter (NKCC) and Cl− channel 2 (ClC2) regulates active K+ secretion. K+ entering cells via basolateral NKCC (K+ loader) exits via apical BK channels. K+ entering via Na+,K+‐ATPase also contributes to apical BK channel‐mediated K+ secretion. Continuous K+ secretion depends on CLC2 and Na+,K+‐ATPase maintaining low intracellular levels of Cl− and Na+, respectively. cAMP activates both basolateral NKCC and apical BK channel. Mucosal iberiotoxin IbTX inhibits active K+ secretion. [Reproduced, with permission, from (159).]


Figure 6. Colonic epithelial cell models for basolateral membrane K+ channel‐regulated transport processes. (A) Under basal conditions, K+ recycling across basolateral membranes via intermediate conductance K+ (IK) channels operating in concert with Na+,K+‐ATPase, contributes to the favorable electrochemical gradient (reflecting high intracellular K+ and low intracellular Na+ concentrations, and a negative membrane potential) necessary for the secondary Na+ absorption mediated by apical Na+‐H+ exchanger isoforms 2 and 3 (NHE2/NHE3) and epithelial Na+ channel (ENaC). NHE2 and NHE3 mediate electroneutral Na+ absorption, while ENaC mediates electrogenic Na+ absorption. (B) Under stimulated condition (e.g., cholera), apical Cl− exit via CFTR (cystic fibrosis transmembrane regulator) Cl− channels following Na+‐K+‐2Cl− (NKCC) transporter‐mediated basolateral Cl− uptake tends to depolarize cells. This is counter‐balanced by the hyperpolarizing effect of K+ exit through basolateral IK channels, thus maintaining the electrical gradient required for sustained Cl− secretion.


Figure 7. Effect of cellular cAMP increased by serosal addition of forskolin (FSK, adenylate cyclase activator) on K+ fluxes in the presence and absence of mucosal VO4 (P‐type ATPase inhibitor) in rat distal colon. (A) In the absence of mucosal VO4, FSK significantly inhibits active K+ absorption (i.e., net K+ absorption) by stimulating s‐m K+ fluxes. (B) Presence of 1 mmol/L mucosal VO4 unmasks FKS‐induced active K+ secretion. It is to be noted that mucosal VO4 also inhibits basal K+ absorption in normal colon (see Fig. 11). Mucosal to serosal (m‐s) and serosal to mucosal (s‐m) 86Rb+ fluxes (K+ surrogate) were measured under voltage clamp condition in the absence (green bars) and presence (red bars) of forskolin. Net K+ fluxes were calculated by subtracting s‐m fluxes from m‐s fluxes. Positive and negative fluxes represent active K+ absorption and active K+ secretion, respectively. *P < 0.001—compared to respective fluxes in the absence of FSK; £P < 0.05—compared to in the absence of FSK. [Reproduced, with permission, from ref. (159).]


Figure 8. Immunogold labeling of intermediate conductance K+ (IK) channels in colonic surface epithelial cells of normal rat distal colon (RtDC) and normal human colon (HuC). Cryosemithin sections were prepared and trypan blue‐stained for orientation (left column of each panel). Tissue specimens were ultratrimmed for cryothin sectioning, focusing on small areas of interest in the colonic surface epithelium to characterize plasma membrane domain‐specific localization of IK channel proteins at the ultrastructural level. Cryothin sections were immunolabeled with anti‐IKabc and detected with a secondary donkey anti‐rabbit 10 nm gold‐labeled antibody. Anti‐IKabc localized IK‐like proteins in apical [A], and lateral [L] plasma membrane domains of rat and human colonic epithelial cells, but not in basal plasma membranes [B] of surface epithelial enterocytes. These results using high‐resolution immunogold electron microscopy confirm our earlier results using confocal microscopy. [S] Surface epithelium; [C] crypts; [n] nucleus; [bm] basal plasma membrane. Images were acquired either at 400× primary magnification (cryosemithin section, bar = 20 µm) by light microscopy, or at 21,000× primary magnification (cryothin sections, bar = 200 nm) by electron microscopy. Similar results were obtained with two and three different human and rat tissues, respectively. [Reproduced, with permission, from ref. (12).]


Figure 9. Indirect immunofluorescence imaging of intermediate conductance K+ (IK) channel protein in cRNA‐injected Xenopus oocytes. Anti‐IKabc antibody localized IK channel proteins to the plasma membrane of IKb cRNA‐injected oocytes (IKb), but not water injected (control) oocytes. IK protein was identified only in the cytoplasm, but not in the plasm membrane of IKc cRNA‐injected oocytes (IKc). Plasma membrane targeting of IK protein was substantially enhanced in oocytes coinjected with IKc and the BKβ1 subunit (i.e., large conductance K+ channel β‐subunit) cRNAs (IKc + BKβ1). Arrowheads indicate the absence (or minimal presence) of IK cahnnel proteins (left panels), while arrows indicate the presence of IK channel proteins (right panels) on the plasma membrane of oocytes. Fluorescence images were acquired using Nikon light microscope. Bar = 0.1 mm. [Adapted, with permission, from ref. (12).]


Figure 10. Mucosal DC‐EBIO [intermediate conductance K+ (IK) channel opener] activates IK channel mediated K+ secretion in normal rat distal colon. Minimal K+ secretion is present under basal conditions. Mucosal DC‐EBIO stimulates active K+ secretion. Mucosal TRAM‐34 (IK channel blocker) inhibits DC‐EBIO‐stimulated K+ secretion. DC‐EBIO‐stimulated K+ secretion is not inhibited by mucosal iberiotoxin IbTX, large conductance K+ (BK) channel blocker). [Reproduced, with permission, from ref. (124).]


Figure 11. Active K+ transport in normal and aldosterone‐treated (dietary Na+ depleted) rat distal colon. Net K+ transport was determined from the difference between mucosal to serosal (m‐s) and serosal to mucosal (s‐m) unidirectional fluxes measured under voltage clamp conditions. Net positive value represent active K+ absorption, while net negative value represent active K+ secretion. (A) Active K+ absorption present in normal rat distal colon (green bars) was inhibited by mucosal vanadate (VO4; P‐type ATPase inhibitor; red bars). (B) Active K+ secretion in aldosterone‐treated rat distal colon was further stimulated by mucosal VO4. *P < 0.001—compared to control; £P < 0.001—compared to control; ‡P < 0.001—compared to control. [Reproduced, with permission, from ref. (176).]


Figure 12. Effect of actinomycin D on aldosterone‐induced Isc in normal rat distal colon in vitro. (A) Normal rat distal colonic mucosal layers were mounted under voltage clamp condition in Ussing chambers. Immediately after mounting, either aldosterone (aldo) or aldosterone plus actinomycin D (transcriptional inhibitor) (aldo/act‐D) was added to the serosal bath. Short circuit current (Isc) was measured for up to 9 h. At the end of 8½ h, 10 µmol/L amiloride was added to mucosal bath. Enhanced Isc and inhbition of Isc by amiloride indicates that aldosterone induced epithelial Na+ channel (ENaC)‐mediated Na+ absorption (aldo). Absence of amiloride‐sensitive Isc in the presence of actinomycin D (aldo/act‐D) indicates that aldosterone‐induced ENaC‐mediated Na+ absorption is regulated at transcriptional level. (B) RT‐qPCR analyses indicated that aldosterone enhanced the abundance of large conductance K+ channel α‐subunit (BKα)‐specific mRNA (aldo), while this change was prevented by actinomycin D (aldo/act‐D). (C) K+ fluxes measured under voltage clamp condition indicate that aldosterone stimulated active K+ secretion (aldo), whereas this response was blocked by actinomycin D (aldo/act‐D). [Reproduced, with permission, from ref. (176).]


Figure 13. Dextran sulfate sodium (DSS)‐induced inflammation stimulates active K+ secretion and abolishes agonist (cAMP and Ca2+)‐stimulated Cl− secretion in rat distal colon. (A) Positive Isc (short circuit current) represents the presence of anion (Cl−/HCO3−) secretion under basal conditions. Increasing intracellular cAMP by forskolin (FSK; adenylate cyclase activator) stimulated active Cl− secretion. Increasing intracellular Ca2+ by carbachol (CCH; adrenergic agonist; FSK/CCH) further transiently stimulated active Cl− secretion. (B) Negative Isc indicates induced cation secretion and absence of anion secretion under basal conditions in DSS‐inflamed colon. The minimal increase in Isc induced by FSK, and the absence of a FSK/CCH‐induced Isc, indicated that Cl− secretory processes were abolished in DSS‐inflamed colon. (C) In the presence of mucosal ortho‐VO4 (H+,K+‐ATPase inhibitor), minimal K+ absorption was present in normal colon (control). In normal colon, FSK stimulated active K+ secretion, while FSK/CCH had no additional effect on K+ secretion. (D) In DSS‐inflamed colon (control), active K+ secretion was present under basal conditions, but neither FSK nor FSK/CCH stimulated active K+ secretion. [Reproduced, with permission, from ref. (94).]
References
 1.Abrahamse SI, De Jonge HR, Bindels RJ, Van Os CH. Two distinct K(+)‐ATPase activities in rabbit distal colon. Biochem Biophys Res Commun 207: 1003‐1008, 1995.
 2.Abrahamse SL, Bindels RJ, van Os CH. The colon carcinoma cell line Caco‐2 contains an H+/K(+)‐ATPase that contributes to intracellular pH regulation. Pflugers Arch 421: 591‐597, 1992.
 3.Agarwal R, Afzalpurkar R, Fordtran JS. Pathophysiology of potassium absorption and secretion by the human intestine. Gastroenterology 107: 548‐571, 1994.
 4.Al‐Hazza A, Linley J, Aziz Q, Hunter M, Sandle G. Upregulation of basolateral small conductance potassium channels (KCNQ1/KCNE3) in ulcerative colitis. Biochem Biophys Res Commun 470: 473‐478, 2016.
 5.Al‐Hazza A, Linley JE, Aziz Q, Maclennan KA, Hunter M, Sandle GI. Potential role of reduced basolateral potassium (IKCa3.1) channel expression in the pathogenesis of diarrhoea in ulcerative colitis. J Pathol 226: 463‐470, 2012.
 6.Almassy J, Won JH, Begenisich TB, Yule DI. Apical Ca2+‐activated potassium channels in mouse parotid acinar cells. J Gen Physiol 139: 121‐133, 2012.
 7.Amasheh S, Barmeyer C, Koch CS, Tavalali S, Mankertz J, Epple HJ, Gehring MM, Florian P, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD. Cytokine‐dependent transcriptional down‐regulation of epithelial sodium channel in ulcerative colitis. Gastroenterology 126: 1711‐1720, 2004.
 8.Archampong EQ, Harris J, Clark CG. The absorption and secretion of water and electrolytes across the healthy and the diseased human colonic mucosa measured in vitro. Gut 13: 880‐886, 1972.
 9.Asano S, Hoshina S, Nakaie Y, Watanabe T, Sato M, Suzuki Y, Takeguchi N. Functional expression of putative H+‐K+‐ATPase from guinea pig distal colon. Am J Physiol 275: C669‐C674, 1998.
 10.Atwell JD, Duthie HL. The absorption of water, sodium, and potassium from the ileum of humans showing the effects of regional enteritis. Gastroenterology 46: 16‐22, 1964.
 11.Barada K, Okolo C, Field M, Cortas N. Na,K‐ATPase in diabetic rat small intestine. Changes at protein and mRNA levels and role of glucagon. J Clin Invest 93: 2725‐2731, 1994.
 12.Barmeyer C, Rahner C, Yang Y, Sigworth FJ, Binder HJ, Rajendran VM. Cloning and identification of tissue‐specific expression of KCNN4 splice variants in rat colon. Am J Physiol Cell Physiol 299: C251‐C263, 2010.
 13.Barnaby CF, Edmonds CJ. Use of a miniature GM counter and a whole body counter in the study of potassium transport by the colon of normal, sodium‐depleted and adrenalectomized rats in vivo. J Physiol 205: 647‐665, 1969.
 14.Bastl CP, Barnett CA, Schmidt TJ, Litwack G. Glucocorticoid stimulation of sodium absorption in colon epithelia is mediated by corticosteroid IB receptor. J Biol Chem 259: 1186‐1195, 1984.
 15.Bastl CP, Hayslett JP. The cellular action of aldosterone in target epithelia. Kidney Int 42: 250‐264, 1992.
 16.Behrens R, Nolting A, Reimann F, Schwarz M, Waldschutz R, Pongs O. hKCNMB3 and hKCNMB4, cloning and characterization of two members of the large‐conductance calcium‐activated potassium channel beta subunit family. FEBS Lett 474: 99‐106, 2000.
 17.Berkefeld H, Fakler B, Schulte U. Ca2+‐activated K+ channels: From protein complexes to function. Physiol Rev 90: 1437‐1459, 2010.
 18.Billich CO, Levitan R. Effects of sodium concentration and osmolality on water and electrolyte absorption form the intact human colon. J Clin Invest 48: 1336‐1347, 1969.
 19.Binder HJ, Murer H. Potassium/proton exchange in brush‐border membrane of rat ileum. J Membr Biol 91: 77‐84, 1986.
 20.Binder HJ, Sandle GI, Rajendran VM. Colonic fluid and electrolyte transport in health and disease. In: Phillips SF, Shorter, R., Pemberton, W, editors. The Large Intestine. New York: Raven Press, 1991, pp. 141‐168.
 21.Binder HJ, Sangan P, Rajendran VM. Physiological and molecular studies of colonic H+,K+‐ATPase. Semin Nephrol 19: 405‐414, 1999.
 22.Binder HJ, White A, Whiting D, Hayslett J. Demonstration of specific high affinity receptors for aldosterone in cytosol of rat colon. Endocrinology 118: 628‐631, 1986.
 23.Blanco G, Mercer RW. Isozymes of the Na‐K‐ATPase: Heterogeneity in structure, diversity in function. Am J Physiol 275: F633‐F650, 1998.
 24.Bowley KA, Morton MJ, Hunter M, Sandle GI. Non‐genomic regulation of intermediate conductance potassium channels by aldosterone in human colonic crypt cells. Gut 52: 854‐860, 2003.
 25.Breitwieser GE. Mechanisms of K+ channel regulation. J Membr Biol 152: 1‐11, 1996.
 26.Brenner R, Jegla TJ, Wickenden A, Liu Y, Aldrich RW. Cloning and functional characterization of novel large conductance calcium‐activated potassium channel beta subunits, hKCNMB3 and hKCNMB4. J Biol Chem 275: 6453‐6461, 2000.
 27.Burckhardt BC, Gogelein H. Small and maxi K+ channels in the basolateral membrane of isolated crypts from rat distal colon: Single‐channel and slow whole‐cell recordings. Pflugers Arch 420: 54‐60, 1992.
 28.Butler A, Tsunoda S, McCobb DP, Wei A, Salkoff L. mSlo, a complex mouse gene encoding “maxi” calcium‐activated potassium channels. Science 261: 221‐224, 1993.
 29.Butterfield I, Warhurst G, Jones MN, Sandle GI. Characterization of apical potassium channels induced in rat distal colon during potassium adaptation. J Physiol 501(Pt 3): 537‐547, 1997.
 30.Catalan M, Cornejo I, Figueroa CD, Niemeyer MI, Sepulveda FV, Cid LP. ClC‐2 in guinea pig colon: mRNA, immunolabeling, and functional evidence for surface epithelium localization. Am J Physiol Gastrointest Liver Physiol 283: G1004‐G1013, 2002.
 31.Catalan M, Niemeyer MI, Cid LP, Sepulveda FV. Basolateral ClC‐2 chloride channels in surface colon epithelium: Regulation by a direct effect of intracellular chloride. Gastroenterology 126: 1104‐1114, 2004.
 32.Catalan MA, Pena‐Munzenmayer G, Melvin JE. Ca(2)(+)‐dependent K(+) channels in exocrine salivary glands. Cell Calcium 55: 362‐368, 2014.
 33.Chen L, Tuo B, Dong H. Regulation of intestinal glucose absorption by ion channels and transporters. Nutrients 8: pii: E43, 2016.
 34.Chiu YH, Alvarez‐Baron C, Kim EY, Dryer SE. Dominant‐negative regulation of cell surface expression by a pentapeptide motif at the extreme COOH terminus of an Slo1 calcium‐activated potassium channel splice variant. Mol Pharmacol 77: 497‐507.
 35.Chow DC, Forte JG. Functional significance of the beta‐subunit for heterodimeric P‐type ATPases. J Exp Biol 198: 1‐17, 1995.
 36.Codina J, Delmas‐Mata JT, DuBose TD, Jr. The alpha‐subunit of the colonic H+,K+‐ATPase assembles with beta1‐Na+,K+‐ATPase in kidney and distal colon. J Biol Chem 273: 7894‐7899, 1998.
 37.Codina J, Kone BC, Delmas‐Mata JT, DuBose TD, Jr. Functional expression of the colonic H+,K+‐ATPase alpha‐subunit. Pharmacologic properties and assembly with X+,K+‐ATPase beta‐subunits. J Biol Chem 271: 29759‐29763, 1996.
 38.Cougnon M, Planelles G, Crowson MS, Shull GE, Rossier BC, Jaisser F. The rat distal colon P‐ATPase alpha subunit encodes a ouabain‐sensitive H+, K+‐ATPase. J Biol Chem 271: 7277‐7280, 1996.
 39.Cox DH, Aldrich RW. Role of the beta1 subunit in large‐conductance Ca(2+)‐activated K(+) channel gating energetics. Mechanisms of enhanced Ca(2+) sensitivity. J Gen Physiol 116: 411‐432, 2000.
 40.Crowson MS, Shull GE. Isolation and characterization of a cDNA encoding the putative distal colon H+,K(+)‐ATPase. Similarity of deduced amino acid sequence to gastric H+,K(+)‐ATPase and Na+,K(+)‐ATPase and mRNA expression in distal colon, kidney, and uterus. J Biol Chem 267: 13740‐13748, 1992.
 41.Dames P, Bergann T, Fromm A, Bucker R, Barmeyer C, Krug SM, Fromm M, Schulzke JD. Interleukin‐13 affects the epithelial sodium channel in the intestine by coordinated modulation of STAT6 and p38 MAPK activity. J Physiol 593: 5269‐5282, 2015.
 42.Davis GR, Santa Ana CA, Morawski SG, Fordtran JS. Permeability characteristics of human jejunum, ileum, proximal colon and distal colon: Results of potential difference measurements and unidirectional fluxes. Gastroenterology 83: 844‐850, 1982.
 43.Dedek K, Waldegger S. Colocalization of KCNQ1/KCNE channel subunits in the mouse gastrointestinal tract. Pflugers Arch 442: 896‐902, 2001.
 44.Deitrick JE, Whedon GD, Shorr E. Effects of immobilization upon various metabolic and physiologic functions of normal men. Am J Med 4: 3‐36, 1948.
 45.Del Castillo JR, Rajendran VM, Binder HJ. Apical membrane localization of ouabain‐sensitive K(+)‐activated ATPase activities in rat distal colon. Am J Physiol 261: G1005‐G1011, 1991.
 46.Demolombe S, Franco D, de Boer P, Kuperschmidt S, Roden D, Pereon Y, Jarry A, Moorman AF, Escande D. Differential expression of KvLQT1 and its regulator IsK in mouse epithelia. Am J Physiol Cell Physiol 280: C359‐C372, 2001.
 47.Devor DC, Frizzell RA. Modulation of K+ channels by arachidonic acid in T84 cells. II. Activation of a Ca(2+)‐independent K+ channel. Am J Physiol 274: C149‐C160, 1998.
 48.Devor DC, Singh AK, Gerlach AC, Frizzell RA, Bridges RJ. Inhibition of intestinal Cl‐ secretion by clotrimazole: Direct effect on basolateral membrane K+ channels. Am J Physiol 273: C531‐C540, 1997.
 49.Devroede GJ, Phillips SF. Conservation of sodium, chloride, and water by the human colon. Gastroenterology 56: 101‐109, 1969.
 50.Dharmsathaphorn K, Pandol SJ. Mechanism of chloride secretion induced by carbachol in a colonic epithelial cell line. J Clin Invest 77: 348‐354, 1986.
 51.Diamond JM, Ehrlich BE, Morawski SG, Santa Ana CA, Fordtran JS. Lithium absorption in tight and leaky segments of intestine. J Membr Biol 72: 153‐159, 1983.
 52.Dorge A, Beck FX, Rechkemmer G. Cellular site of active K absorption in the guinea‐pig distal colonic epithelium. Pflugers Arch 436: 280‐288, 1998.
 53.Duthie HL, Atwell JD. The absorption of water, sodium, and potassium in the large intestine with particular reference to the effects of villous papillomas. Gut 4: 373‐377, 1963.
 54.Dworetzky SI, Boissard CG, Lum‐Ragan JT, McKay MC, Post‐Munson DJ, Trojnacki JT, Chang CP, Gribkoff VK. Phenotypic alteration of a human BK (hSlo) channel by hSlobeta subunit coexpression: Changes in blocker sensitivity, activation/relaxation and inactivation kinetics, and protein kinase A modulation. J Neurosci 16: 4543‐4550, 1996.
 55.Edmonds CJ. Transport of sodium and secretion of potassium and bicarbonate by the colon of normal and sodium‐depleted rats. J Physiol 193: 589‐602, 1967.
 56.Edmonds CJ. Kinetics of potassium in colonic mucosa of normal and sodium‐depleted rats. J Physiol 203: 533‐554, 1969.
 57.Fejes‐Toth G, Rusvai E, Longo KA, Naray‐Fejes‐Toth A. Expression of colonic H‐K‐ATPase mRNA in cortical collecting duct: Regulation by acid/base balance. Am J Physiol 269: F551‐F557, 1995.
 58.Field M. Intestinal ion transport and the pathophysiology of diarrhea. J Clin Invest 111: 931‐943, 2003.
 59.Fisher KA, Binder HJ, Hayslett JP. Potassium secretion by colonic mucosal cells after potassium adaptation. Am J Physiol 231: 987‐994, 1976.
 60.Flores CA, Melvin JE, Figueroa CD, Sepulveda FV. Abolition of Ca2+‐mediated intestinal anion secretion and increased stool dehydration in mice lacking the intermediate conductance Ca2+‐dependent K+ channel Kcnn4. J Physiol 583: 705‐717, 2007.
 61.Fodor AA, Aldrich RW. Convergent evolution of alternative splices at domain boundaries of the BK channel. Annu Rev Physiol 71: 19‐36, 2009.
 62.Foster ES, Hayslett JP, Binder HJ. Colonic potassium transport. Kroc Found Ser 17: 47‐63, 1984.
 63.Foster ES, Hayslett JP, Binder HJ. Mechanism of active potassium absorption and secretion in the rat colon. Am J Physiol 246: G611‐G617, 1984.
 64.Foster ES, Jones WJ, Hayslett JP, Binder HJ. Role of aldosterone and dietary potassium in potassium adaptation in the distal colon of the rat. Gastroenterology 88: 41‐46, 1985.
 65.Foster ES, Sandle GI, Hayslett JP, Binder HJ. Cyclic adenosine monophosphate stimulates active potassium secretion in the rat colon. Gastroenterology 84: 324‐330, 1983.
 66.Foster ES, Sandle GI, Hayslett JP, Binder HJ. Dietary potassium modulates active potassium absorption and secretion in rat distal colon. Am J Physiol 251: G619‐G626, 1986.
 67.Fuller PJ, Verity K. Mineralocorticoid receptor gene expression in the gastrointestinal tract: Distribution and ontogeny. J Steroid Biochem 36: 263‐267, 1990.
 68.Furness JB, Robbins HL, Selmer IS, Hunne B, Chen MX, Hicks GA, Moore S, Neylon CB. Expression of intermediate conductance potassium channel immunoreactivity in neurons and epithelial cells of the rat gastrointestinal tract. Cell Tissue Res 314: 179‐189, 2003.
 69.Geering K. Functional roles of Na,K‐ATPase subunits. Curr Opin Nephrol Hypertens 17: 526‐532, 2008.
 70.Grahammer F, Warth R, Barhanin J, Bleich M, Hug MJ. The small conductance K+ channel, KCNQ1: Expression, function, and subunit composition in murine trachea. J Biol Chem 276: 42268‐42275, 2001.
 71.Greig ER, Boot‐Handford RP, Mani V, Sandle GI. Decreased expression of apical Na+ channels and basolateral Na+, K+‐ATPase in ulcerative colitis. J Pathol 204: 84‐92, 2004.
 72.Grishin AV, Caplan MJ. ATP1AL1, a member of the non‐gastric H,K‐ATPase family, functions as a sodium pump. J Biol Chem 273: 27772‐27778, 1998.
 73.Grishin AV, Sverdlov VE, Kostina MB, Modyanov NN. Cloning and characterization of the entire cDNA encoded by ATP1AL1–a member of the human Na,K/H,K‐ATPase gene family. FEBS Lett 349: 144‐150, 1994.
 74.Gustin MC, Goodman DB. Isolation of brush‐border membrane from the rabbit descending colon epithelium. Partial characterization of a unique K+‐activated ATPase. J Biol Chem 256: 10651‐10656, 1981.
 75.Halm DR, Dawson DC. Potassium transport by turtle colon: Active secretion and active absorption. Am J Physiol 246: C315‐C322, 1984.
 76.Halm DR, Frizzell RA. Active K transport across rabbit distal colon: Relation to Na absorption and Cl secretion. Am J Physiol 251: C252‐C267, 1986.
 77.Halm DR, Halm ST. Aldosterone stimulates K secretion prior to onset of Na absorption in guinea pig distal colon. Am J Physiol 266: C552‐C558, 1994.
 78.Harris J, Shields R. Absorption and secretion of water and electrolytes by the intact human colon in diffuse untreated proctocolitis. Gut 11: 27‐33, 1970.
 79.Hawker PC, Mashiter KE, Turnberg LA. Mechanisms of transport of Na, Cl, and K in the human colon. Gastroenterology 74: 1241‐1247, 1978.
 80.Hawker PC, McKay JS, Turnberg LA. Electrolyte transport across colonic mucosa from patients with inflammatory bowel disease. Gastroenterology 79: 508‐511, 1980.
 81.Hay‐Schmidt A, Grunnet M, Abrahamse SL, Knaus HG, Klaerke DA. Localization of Ca2+‐activated big‐conductance K+ channels in rabbit distal colon. Pflugers Arch 446: 61‐68, 2003.
 82.Hayes CP, Jr., McLeod ME, Robinson RR. An extravenal mechanism for the maintenance of potassium balance in severe chronic renal failure. Trans Assoc Am Physicians 80: 207‐216, 1967.
 83.Hayslett JP, Binder HJ. Mechanism of potassium adaptation. Am J Physiol 243: F103‐F112, 1982.
 84.Hayslett JP, Myketey N, Binder HJ, Aronson PS. Mechanism of increased potassium secretion in potassium loading and sodium deprivation. Am J Physiol 239: F378‐F382, 1980.
 85.Heitzmann D, Warth R. No potassium, no acid: K+ channels and gastric acid secretion. Physiology (Bethesda) 22: 335‐341, 2007.
 86.Heitzmann D, Warth R. Physiology and pathophysiology of potassium channels in gastrointestinal epithelia. Physiol Rev 88: 1119‐1182, 2008.
 87.Ikuma M, Kashgarian M, Binder HJ, Rajendran VM. Differential regulation of NHE isoforms by sodium depletion in proximal and distal segments of rat colon. Am J Physiol 276: G539‐G549, 1999.
 88.Jaisser F, Escoubet B, Coutry N, Eugene E, Bonvalet JP, Farman N. Differential regulation of putative K(+)‐ATPase by low‐K+ diet and corticosteroids in rat distal colon and kidney. Am J Physiol 270: C679‐C687, 1996.
 89.Jaisser F, Horisberger JD, Geering K, Rossier BC. Mechanisms of urinary K+ and H+ excretion: Primary structure and functional expression of a novel H,K‐ATPase. J Cell Biol 123: 1421‐1429, 1993.
 90.Jaisser F, Jaunin P, Geering K, Rossier BC, Horisberger JD. Modulation of the Na,K‐pump function by beta subunit isoforms. J Gen Physiol 103: 605‐623, 1994.
 91.Johnson BB, Lieberman AH, Mulrow PJ. Aldosterone excretion in normal subjects depleted of sodium and potassium. J Clin Invest 36: 757‐766, 1957.
 92.Joiner WJ, Basavappa S, Vidyasagar S, Nehrke K, Krishnan S, Binder HJ, Boulpaep EL, Rajendran VM. Active K+ secretion through multiple KCa‐type channels and regulation by IKCa channels in rat proximal colon. Am J Physiol Gastrointest Liver Physiol 285: G185‐G196, 2003.
 93.Joiner WJ, Wang LY, Tang MD, Kaczmarek LK. hSK4, a member of a novel subfamily of calcium‐activated potassium channels. Proc Natl Acad Sci U S A 94: 11013‐11018, 1997.
 94.Kanthesh BM, Sandle GI, Rajendran VM. Enhanced K(+) secretion in dextran sulfate‐induced colitis reflects upregulation of large conductance apical K(+) channels (BK; Kcnma1). Am J Physiol Cell Physiol 305: C972‐C980, 2013.
 95.Kashgarian M, Taylor CR, Binder HJ, Hayslett JP. Amplification of cell membrane surface in potassium adaptation. Lab Invest 42: 581‐588, 1980.
 96.Kaunitz JD, Sachs G. Identification of a vanadate‐sensitive potassium‐dependent proton pump from rabbit colon. J Biol Chem 261: 14005‐14010, 1986.
 97.Kliger AS, Binder HJ, Bastl C, Hayslett JP. Demonstration of active potassium transport in the mammalian colon. J Clin Invest 67: 1189‐1196, 1981.
 98.Kunzelmann K, Hubner M, Schreiber R, Levy‐Holzman R, Garty H, Bleich M, Warth R, Slavik M, von Hahn T, Greger R. Cloning and function of the rat colonic epithelial K+ channel KVLQT1. J Membr Biol 179: 155‐164, 2001.
 99.Kunzelmann K, Mall M. Electrolyte transport in the mammalian colon: Mechanisms and implications for disease. Physiol Rev 82: 245‐289, 2002.
 100.Kwon SH, Guggino WB. Multiple sequences in the C terminus of MaxiK channels are involved in expression, movement to the cell surface, and apical localization. Proc Natl Acad Sci U S A 101: 15237‐15242, 2004.
 101.Lee J, Rajendran VM, Mann AS, Kashgarian M, Binder HJ. Functional expression and segmental localization of rat colonic K‐adenosine triphosphatase. J Clin Invest 96: 2002‐2008, 1995.
 102.Lee MP, Ravenel JD, Hu RJ, Lustig LR, Tomaselli G, Berger RD, Brandenburg SA, Litzi TJ, Bunton TE, Limb C, Francis H, Gorelikow M, Gu H, Washington K, Argani P, Goldenring JR, Coffey RJ, Feinberg AP. Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. J Clin Invest 106: 1447‐1455, 2000.
 103.Levin RJ, Newey H, Smyth DH. The effects of adrenalectomy and fasting on intestinal function in the rat. J Physiol 177: 58‐73, 1965.
 104.Liao T, Wang L, Halm ST, Lu L, Fyffe RE, Halm DR. K+ channel KVLQT1 located in the basolateral membrane of distal colonic epithelium is not essential for activating Cl‐ secretion. Am J Physiol Cell Physiol 289: C564‐C575, 2005.
 105.Linley J, Loganathan A, Kopanati S, Sandle GI, Hunter M. Evidence that two distinct crypt cell types secrete chloride and potassium in human colon. Gut 63: 472‐479, 2014.
 106.Lippiat JD, Standen NB, Harrow ID, Phillips SC, Davies NW. Properties of BK(Ca) channels formed by bicistronic expression of hSloalpha and beta1‐4 subunits in HEK293 cells. J Membr Biol 192: 141‐148, 2003.
 107.Lomax RB, McNicholas CM, Lombes M, Sandle GI. Aldosterone‐induced apical Na+ and K+ conductances are located predominantly in surface cells in rat distal colon. Am J Physiol 266: G71‐G82, 1994.
 108.Lomax RB, Sandle GI. Comparison of aldosterone‐ and RU‐28362‐induced apical Na+ and K+ conductances in rat distal colon. Am J Physiol 267: G485‐G493, 1994.
 109.Lomax RB, Warhurst G, Sandle GI. Characteristics of two basolateral potassium channel populations in human colonic crypts. Gut 38: 243‐247, 1996.
 110.Loo DD, Kaunitz JD. Ca2+ and cAMP activate K+ channels in the basolateral membrane of crypt cells isolated from rabbit distal colon. J Membr Biol 110: 19‐28, 1989.
 111.Ma D, Nakata T, Zhang G, Hoshi T, Li M, Shikano S. Differential trafficking of carboxyl isoforms of Ca2+‐gated (Slo1) potassium channels. FEBS Lett 581: 1000‐1008, 2007.
 112.Malik N, Canfield VA, Beckers MC, Gros P, Levenson R. Identification of the mammalian Na,K‐ATPase 3 subunit. J Biol Chem 271: 22754‐22758, 1996.
 113.Mandel KG, McRoberts JA, Beuerlein G, Foster ES, Dharmsathaphorn K. Ba2+ inhibition of VIP‐ and A23187‐stimulated Cl‐ secretion by T84 cell monolayers. Am J Physiol 250: C486‐C494, 1986.
 114.Mathialahan T, Maclennan KA, Sandle LN, Verbeke C, Sandle GI. Enhanced large intestinal potassium permeability in end‐stage renal disease. J Pathol 206: 46‐51, 2005.
 115.Mathialahan T, Sandle GI. Dietary potassium and laxatives as regulators of colonic potassium secretion in end‐stage renal disease. Nephrol Dial Transplant 18: 341‐347, 2003.
 116.McCabe R, Cooke HJ, Sullivan LP. Potassium transport by rabbit descending colon. Am J Physiol 242: C81‐C86, 1982.
 117.McDonough AA, Geering K, Farley RA. The sodium pump needs its beta subunit. FASEB J 4: 1598‐1605, 1990.
 118.McNamara B, Winter DC, Cuffe JE, O'Sullivan GC, Harvey BJ. Basolateral K+ channel involvement in forskolin‐activated chloride secretion in human colon. J Physiol 519(Pt 1): 251‐260, 1999.
 119.McNicholas CM, Fraser G, Sandle GI. Properties and regulation of basolateral K+ channels in rat duodenal crypts. J Physiol 477 (Pt 3): 381‐392, 1994.
 120.Meera P, Wallner M, Song M, Toro L. Large conductance voltage‐ and calcium‐dependent K+ channel, a distinct member of voltage‐dependent ion channels with seven N‐terminal transmembrane segments (S0‐S6), an extracellular N terminus, and an intracellular (S9‐S10) C terminus. Proc Natl Acad Sci U S A 94: 14066‐14071, 1997.
 121.Meneton P, Schultheis PJ, Greeb J, Nieman ML, Liu LH, Clarke LL, Duffy JJ, Doetschman T, Lorenz JN, Shull GE. Increased sensitivity to K+ deprivation in colonic H,K‐ATPase‐deficient mice. J Clin Invest 101: 536‐542, 1998.
 122.Morris AP, Gallacher DV, Lee JA. A large conductance, voltage‐ and calcium‐activated K+ channel in the basolateral membrane of rat enterocytes. FEBS Lett 206: 87‐92, 1986.
 123.Nakajo K, Kubo Y. KCNQ1 channel modulation by KCNE proteins via the voltage‐sensing domain. J Physiol 593: 2617‐2625, 2015.
 124.Nanda Kumar NS, Singh SK, Rajendran VM. Mucosal potassium efflux mediated via Kcnn4 channels provides the driving force for electrogenic anion secretion in colon. Am J Physiol Gastrointest Liver Physiol 299: G707‐G714, 2010.
 125.Neylon CB, Lang RJ, Fu Y, Bobik A, Reinhart PH. Molecular cloning and characterization of the intermediate‐conductance Ca(2+)‐activated K(+) channel in vascular smooth muscle: Relationship between K(Ca) channel diversity and smooth muscle cell function. Circ Res 85: e33‐e43, 1999.
 126.O'Hara B, Alvarez de la Rosa D, Rajendran VM. Multiple mineralocorticoid response elements localized in different introns regulate intermediate conductance K+ (Kcnn4) channel expression in the rat distal colon. PLoS One 9: e98695, 2014.
 127.Pandiyan V, Rajendran VM, Binder HJ. Mucosal ouabain and Na+ inhibit active Rb+(K+) absorption in normal and sodium‐depleted rat distal colon. Gastroenterology 102: 1846‐1853, 1992.
 128.Perrone RD, McBride DE. Aldosterone and PCO2 enhance rubidium absorption in rat distal colon. Am J Physiol 254: G898‐G906, 1988.
 129.Perry MD, Rajendran VM, MacLennan KA, Sandle GI. Segmental differences in upregulated apical potassium channels in mammalian colon during potassium adaptation. Am J Physiol Gastrointest Liver Physiol 311: G785‐G793, 2016.
 130.Perry MD, Sandle GI. Regulation of colonic apical potassium (BK) channels by cAMP and somatostatin. Am J Physiol Gastrointest Liver Physiol 297: G159‐G167, 2009.
 131.Pestov NB, Korneenko TV, Shakhparonov MI, Shull GE, Modyanov NN. Loss of acidification of anterior prostate fluids in Atp12a‐null mutant mice indicates that nongastric H‐K‐ATPase functions as proton pump in vivo. Am J Physiol Cell Physiol 291: C366‐C374, 2006.
 132.Pestov NB, Romanova LG, Korneenko TV, Egorov MV, Kostina MB, Sverdlov VE, Askari A, Shakhparonov MI, Modyanov NN. Ouabain‐sensitive H,K‐ATPase: Tissue‐specific expression of the mammalian genes encoding the catalytic alpha subunit. FEBS Lett 440: 320‐324, 1998.
 133.Phillips SF, Giller J. The contribution of the colon to electrolyte and water conservation in man. J Lab Clin Med 81: 733‐746, 1973.
 134.Plass H, Gridl A, Turnheim K. Absorption and secretion of potassium by rabbit descending colon. Pflugers Arch 406: 509‐519, 1986.
 135.Pongs O, Schwarz JR. Ancillary subunits associated with voltage‐dependent K+ channels. Physiol Rev 90: 755‐796, 2010.
 136.Pressley L, Funder JW. Glucocorticoid and mineralocorticoid receptors in gut mucosa. Endocrinology 97: 588‐596, 1975.
 137.Preston P, Wartosch L, Gunzel D, Fromm M, Kongsuphol P, Ousingsawat J, Kunzelmann K, Barhanin J, Warth R, Jentsch TJ. Disruption of the K+ channel beta‐subunit KCNE3 reveals an important role in intestinal and tracheal Cl‐ transport. J Biol Chem 285: 7165‐7175, 2010.
 138.Puntheeranurak S, Schreiber R, Spitzner M, Ousingsawat J, Krishnamra N, Kunzelmann K. Control of ion transport in mouse proximal and distal colon by prolactin. Cell Physiol Biochem 19: 77‐88, 2007.
 139.Rajendran VM, Sangan P, Geibel J, Binder HJ. Ouabain‐sensitive H,K‐ATPase functions as Na,K‐ATPase in apical membranes of rat distal colon. J Biol Chem 275: 13035‐13040, 2000.
 140.Rajendran VM, Singh SK, Geibel J, Binder HJ. Differential localization of colonic H(+)‐K(+)‐ATPase isoforms in surface and crypt cells. Am J Physiol 274: G424‐G429, 1998.
 141.Rask‐Madsen J. Simultaneous measurement of electrical polarization and electrolyte transport by the entire normal and inflamed human colon during in vivo perfusion. Scand J Gastroenterol 8: 327‐336, 1973.
 142.Rechkemmer G, Halm DR. Aldosterone stimulates K secretion across mammalian colon independent of Na absorption. Proc Natl Acad Sci U S A 86: 397‐401, 1989.
 143.Reyes R, Duprat F, Lesage F, Fink M, Salinas M, Farman N, Lazdunski M. Cloning and expression of a novel pH‐sensitive two pore domain K+ channel from human kidney. J Biol Chem 273: 30863‐30869, 1998.
 144.Richards NW, Dawson DC. Single potassium channels blocked by lidocaine and quinidine in isolated turtle colon epithelial cells. Am J Physiol 251: C85‐C89, 1986.
 145.Richards NW, Dawson DC. Selective block of specific K(+)‐conducting channels by diphenylamine‐2‐carboxylate in turtle colon epithelial cells. J Physiol 462: 715‐734, 1993.
 146.Roepke TK, Anantharam A, Kirchhoff P, Busque SM, Young JB, Geibel JP, Lerner DJ, Abbott GW. The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J Biol Chem 281: 23740‐23747, 2006.
 147.Sandle GI. Salt and water absorption in the human colon: A modern appraisal. Gut 43: 294‐299, 1998.
 148.Sandle GI, Binder HJ. Corticosteroids and intestinal ion transport. Gastroenterology 93: 188‐196, 1987.
 149.Sandle GI, Butterfield I, Higgs NB, Warhurst G. Direct inhibitory effect of nicardipine on basolateral K+ channels in human colonic crypts. Pflugers Arch 437: 596‐602, 1999.
 150.Sandle GI, Foster ES, Lewis SA, Binder HJ, Hayslett JP. The electrical basis for enhanced potassium secretion in rat distal colon during dietary potassium loading. Pflugers Arch 403: 433‐439, 1985.
 151.Sandle GI, Gaiger E, Tapster S, Goodship TH. Enhanced rectal potassium secretion in chronic renal insufficiency: Evidence for large intestinal potassium adaptation in man. Clin Sci (Lond) 71: 393‐401, 1986.
 152.Sandle GI, Gaiger E, Tapster S, Goodship TH. Evidence for large intestinal control of potassium homoeostasis in uraemic patients undergoing long‐term dialysis. Clin Sci (Lond) 73: 247‐252, 1987.
 153.Sandle GI, Hayslett JP, Binder HJ. Effect of chronic hyperaldosteronism on the electrophysiology of rat distal colon. Pflugers Arch 401: 22‐26, 1984.
 154.Sandle GI, Hayslett JP, Binder HJ. Effect of glucocorticoids on rectal transport in normal subjects and patients with ulcerative colitis. Gut 27: 309‐316, 1986.
 155.Sandle GI, Higgs N, Crowe P, Marsh MN, Venkatesan S, Peters TJ. Cellular basis for defective electrolyte transport in inflamed human colon. Gastroenterology 99: 97‐105, 1990.
 156.Sandle GI, Hunter M. Apical potassium (BK) channels and enhanced potassium secretion in human colon. QJM 103: 85‐89, 2010.
 157.Sandle GI, McNicholas CM, Lomax RB. Potassium channels in colonic crypts. Lancet 343: 23‐25, 1994.
 158.Sandle GI, Perry MD, Mathialahan T, Linley JE, Robinson P, Hunter M, MacLennan KA. Altered cryptal expression of luminal potassium (BK) channels in ulcerative colitis. J Pathol 212: 66‐73, 2007.
 159.Sandle GI, Rajendran VM. Cyclic AMP‐induced K+ secretion occurs independently of Cl‐ secretion in rat distal colon. Am J Physiol Cell Physiol 303: C328‐C333, 2012.
 160.Sandle GI, Warhurst G, Butterfield I, Higgs NB, Lomax RB. Somatostatin peptides inhibit basolateral potassium channels in human colonic crypts. Am J Physiol 277: G967‐G975, 1999.
 161.Sandle GI, Wills NK, Alles W, Binder HJ. Electrophysiology of the human colon: Evidence of segmental heterogeneity. Gut 27: 999‐1005, 1986.
 162.Sangan P, Brill SR, Sangan S, Forbush B, III, Binder HJ. Basolateral K‐Cl cotransporter regulates colonic potassium absorption in potassium depletion. J Biol Chem 275: 30813‐30816, 2000.
 163.Sangan P, Kolla SS, Rajendran VM, Kashgarian M, Binder HJ. Colonic H‐K‐ATPase beta‐subunit: identification in apical membranes and regulation by dietary K depletion. Am J Physiol 276: C350‐C360, 1999.
 164.Sangan P, Rajendran VM, Mann AS, Kashgarian M, Binder HJ. Regulation of colonic H‐K‐ATPase in large intestine and kidney by dietary Na depletion and dietary K depletion. Am J Physiol 272: C685‐C696, 1997.
 165.Sangan P, Thevananther S, Sangan S, Rajendran VM, Binder HJ. Colonic H‐K‐ATPase alpha‐ and beta‐subunits express ouabain‐insensitive H‐K‐ATPase. Am J Physiol Cell Physiol 278: C182‐C189, 2000.
 166.Sausbier M, Matos JE, Sausbier U, Beranek G, Arntz C, Neuhuber W, Ruth P, Leipziger J. Distal colonic K(+) secretion occurs via BK channels. J Am Soc Nephrol 17: 1275‐1282, 2006.
 167.Schon DA, Silva P, Hayslett JP. Mechanism of potassium excretion in renal insufficiency. Am J Physiol 227: 1323‐1330, 1974.
 168.Schulman G, Miller‐Diener A, Litwack G, Bastl CP. Characterization of the rat colonic aldosterone receptor and its activation process. J Biol Chem 261: 12102‐12108, 1986.
 169.Schultheiss G, Diener M. K+ and Cl‐ conductances in the distal colon of the rat. Gen Pharmacol 31: 337‐342, 1998.
 170.Sepulveda FV, Fargon F, McNaughton PA. K+ and Cl‐ currents in enterocytes isolated from guinea‐pig small intestinal villi. J Physiol 434: 351‐367, 1991.
 171.Shimura S, Hamamoto N, Yoshino N, Kushiyama Y, Fujishiro H, Komazawa Y, Furuta K, Ishihara S, Adachi K, Kinoshita Y. Diarrhea caused by proton pump inhibitor administration: Comparisons among lansoprazole, rabeprazole, and omeprazole. Curr Ther Res Clin Exp 73: 112‐120, 2012.
 172.Shull GE, Greeb J, Lingrel JB. Molecular cloning of three distinct forms of the Na+,K+‐ATPase alpha‐subunit from rat brain. Biochemistry 25: 8125‐8132, 1986.
 173.Shull GE, Lingrel JB. Molecular cloning of the rat stomach (H+ + K+)‐ATPase. J Biol Chem 261: 16788‐16791, 1986.
 174.Siemer C, Gogelein H. Activation of nonselective cation channels in the basolateral membrane of rat distal colon crypt cells by prostaglandin E2. Pflugers Arch 420: 319‐328, 1992.
 175.Simon M, Duong JP, Mallet V, Jian R, MacLennan KA, Sandle GI, Marteau P. Over‐expression of colonic K+ channels associated with severe potassium secretory diarrhoea after haemorrhagic shock. Nephrol Dial Transplant 23: 3350‐3352, 2008.
 176.Singh SK, O'Hara B, Talukder JR, Rajendran VM. Aldosterone induces active K(+) secretion by enhancing mucosal expression of Kcnn4c and Kcnma1 channels in rat distal colon. Am J Physiol Cell Physiol 302: C1353‐C1360, 2012.
 177.Smith PL, McCabe RD. Mechanism and regulation of transcellular potassium transport by the colon. Am J Physiol 247: G445‐G456, 1984.
 178.Sorensen MV, Matos JE, Praetorius HA, Leipziger J. Colonic potassium handling. Pflugers Arch 459: 645‐656, 2010.
 179.Sorensen MV, Matos JE, Sausbier M, Sausbier U, Ruth P, Praetorius HA, Leipziger J. Aldosterone increases KCa1.1 (BK) channel‐mediated colonic K+ secretion. J Physiol 586: 4251‐4264, 2008.
 180.Sorensen MV, Sausbier M, Ruth P, Seidler U, Riederer B, Praetorius HA, Leipziger J. Adrenaline‐induced colonic K+ secretion is mediated by KCa1.1 (BK) channels. J Physiol 588: 1763‐1777, 2010.
 181.Spicer Z, Clarke LL, Gawenis LR, Shull GE. Colonic H(+)‐K(+)‐ATPase in K(+) conservation and electrogenic Na(+) absorption during Na(+) restriction. Am J Physiol Gastrointest Liver Physiol 281: G1369‐G1377, 2001.
 182.Squires RD, Huth EJ. Experimental potassium depletion in normal human subjects. I. Relation of ionic intakes to the renal conservation of potassium. J Clin Invest 38: 1134‐1148, 1959.
 183.Sullivan SK, Smith PL. Active potassium secretion by rabbit proximal colon. Am J Physiol 250: G475‐G483, 1986.
 184.Supplisson S, Loo DD, Sachs G. Diversity of K+ channels in the basolateral membrane of resting Necturus oxyntic cells. J Membr Biol 123: 209‐221, 1991.
 185.Suzuki Y, Kaneko K. Acid secretion in isolated guinea pig colon. Am J Physiol 253: G155‐G164, 1987.
 186.Suzuki Y, Kaneko K. Ouabain‐sensitive H+‐K+ exchange mechanism in the apical membrane of guinea pig colon. Am J Physiol 256: G979‐G988, 1989.
 187.Sverdlov ED, Monastyrskaya GS, Broude NE, Ushkaryov Yu A, Allikmets RL, Melkov AM, Smirnov Yu V, Malyshev IV, Dulobova IE, Petrukhin KE, et al. The family of human Na+,K+‐ATPase genes. No less than five genes and/or pseudogenes related to the alpha‐subunit. FEBS Lett 217: 275‐278, 1987.
 188.Swarts HG, Koenderink JB, Willems PH, De Pont JJ. The non‐gastric H,K‐ATPase is oligomycin‐sensitive and can function as an H+,NH4(+)‐ATPase. J Biol Chem 280: 33115‐33122, 2005.
 189.Swarts HG, Koenderink JB, Willems PH, De Pont JJ. The human non‐gastric H,K‐ATPase has a different cation specificity than the rat enzyme. Biochim Biophys Acta 1768: 580‐589, 2007.
 190.Sweiry JH, Binder HJ. Characterization of aldosterone‐induced potassium secretion in rat distal colon. J Clin Invest 83: 844‐851, 1989.
 191.Sweiry JH, Binder HJ. Active potassium absorption in rat distal colon. J Physiol 423: 155‐170, 1990.
 192.Takahashi Y, Sakai H, Kuragari M, Suzuki T, Tauchi K, Minamimura T, Tsukada K, Asano S, Takeguchi N. Expression of ATP1AL1, a non‐gastric proton pump, in human colorectum. Jpn J Physiol 52: 317‐321, 2002.
 193.Teutsch G, Costerousse G, Deraedt R, Benzoni J, Fortin M, Philibert D. 17 alpha‐alkynyl‐11 beta, 17‐dihydroxyandrostane derivatives: A new class of potent glucocorticoids. Steroids 38: 651‐665, 1981.
 194.Tian L, Duncan RR, Hammond MS, Coghill LS, Wen H, Rusinova R, Clark AG, Levitan IB, Shipston MJ. Alternative splicing switches potassium channel sensitivity to protein phosphorylation. J Biol Chem 276: 7717‐7720, 2001.
 195.Tseng‐Crank J, Foster CD, Krause JD, Mertz R, Godinot N, DiChiara TJ, Reinhart PH. Cloning, expression, and distribution of functionally distinct Ca(2+)‐activated K+ channel isoforms from human brain. Neuron 13: 1315‐1330, 1994.
 196.Turnamian SG, Binder HJ. Aldosterone and glucocorticoid receptor‐specific agonists regulate ion transport in rat proximal colon. Am J Physiol 258: G492‐G498, 1990.
 197.Turnberg LA. Potassium transport in the human small bowel. Gut 12: 811‐818, 1971.
 198.Turnheim K, Plass H, Wyskovsky W. Basolateral potassium channels of rabbit colon epithelium: Role in sodium absorption and chloride secretion. Biochim Biophys Acta 1560: 51‐66, 2002.
 199.Ueda S, Loo DD, Sachs G. Regulation of K+ channels in the basolateral membrane of Necturus oxyntic cells. J Membr Biol 97: 31‐41, 1987.
 200.van Dinter TG, Jr., Fuerst FC, Richardson CT, Ana CA, Polter DE, Fordtran JS, Binder HJ. Stimulated active potassium secretion in a patient with colonic pseudo‐obstruction: A new mechanism of secretory diarrhea. Gastroenterology 129: 1268‐1273, 2005.
 201.Wallner M, Meera P, Toro L. Molecular basis of fast inactivation in voltage and Ca2+‐activated K+ channels: A transmembrane beta‐subunit homolog. Proc Natl Acad Sci U S A 96: 4137‐4142, 1999.
 202.Walters RJ, Sepulveda FV. A basolateral K+ conductance modulated by carbachol dominates the membrane potential of small intestinal crypts. Pflugers Arch 419: 537‐539, 1991.
 203.Warth R, Garcia Alzamora M, Kim JK, Zdebik A, Nitschke R, Bleich M, Gerlach U, Barhanin J, Kim SJ. The role of KCNQ1/KCNE1 K(+) channels in intestine and pancreas: Lessons from the KCNE1 knockout mouse. Pflugers Arch 443: 822‐828, 2002.
 204.Warth R, Hamm K, Bleich M, Kunzelmann K, von Hahn T, Schreiber R, Ullrich E, Mengel M, Trautmann N, Kindle P, Schwab A, Greger R. Molecular and functional characterization of the small Ca(2+)‐regulated K+ channel (rSK4) of colonic crypts. Pflugers Arch 438: 437‐444, 1999.
 205.Warth R, Riedemann N, Bleich M, Van Driessche W, Busch AE, Greger R. The cAMP‐regulated and 293B‐inhibited K+ conductance of rat colonic crypt base cells. Pflugers Arch 432: 81‐88, 1996.
 206.Wills NK, Biagi B. Active potassium transport by rabbit descending colon epithelium. J Membr Biol 64: 195‐203, 1982.
 207.Wilson DR, Ing TS, Metcalfe‐Gibson A, Wrong OM. The chemical composition of faeces in uraemia, as revealed by in‐vivo faecal dialysis. Clin Sci 35: 197‐209, 1968.
 208.Zdebik AA, Cuffe JE, Bertog M, Korbmacher C, Jentsch TJ. Additional disruption of the ClC‐2 Cl(‐) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models. J Biol Chem 279: 22276‐22283, 2004.
 209.Zhang J, Halm ST, Halm DR. Role of the BK channel (KCa1.1) during activation of electrogenic K+ secretion in guinea pig distal colon. Am J Physiol Gastrointest Liver Physiol 303: G1322‐G1334, 2012.

 

 

Further Reading

A comprehensive review of animal colonic H+,K+-ATPase was published by Binder et al (20), while reviews on human and animal colonic K+ channels were published by Sandle and Hunter (153), and Sorensen et al (175), respectively.

Barmeyer C, Rahner C, Yang Y, Sigworth FJ, Binder HJ, and Rajendran VM. Cloning and identification of tissue-specific expression of KCNN4 splice variants in rat colon. Am J Physiol Cell Physiol 299: C251-263, 2010.

Binder HJ, Sangan P, and Rajendran VM. Physiological and molecular studies of colonic H+,K+-ATPase. Semin Nephrol 19: 405-414, 1999.

Del Castillo JR, Rajendran VM, and Binder HJ. Apical membrane localization of ouabain-sensitive K(+)-activated ATPase activities in rat distal colon. Am J Physiol 261: G1005-1011, 1991.

Kanthesh BM, Sandle GI, and Rajendran VM. Enhanced K(+) secretion in dextran sulfate-induced colitis reflects upregulation of large conductance apical K(+) channels (BK; Kcnma1). Am J Physiol Cell Physiol 305: C972-980, 2013.

Singh SK, O'Hara B, Talukder JR, and Rajendran VM. Aldosterone induces active K(+) secretion by enhancing mucosal expression of Kcnn4c and Kcnma1 channels in rat distal colon. Am J Physiol Cell Physiol 302: C1353-1360, 2012.

 

 

 

 

 

Teaching Material

 

 

V. M. Rajendran, G. I. Sandle. Colonic Potassium Absorption and Secretion in Health and Disease. Compr Physiol 8: 2018, 1513-1536.

Didactic Synopsis

Major Teaching Points:

The gastrointestinal (GI) tract has enormous capacity to absorb and secrete K+ to maintain K+ homeostasis.

  1. K+ absorption:
    1. In vivo perfusion studies to evaluate unidirectional K+ fluxes showed passive K+ absorption is mediated by solvent drag in both animal and human colon.
    2. In vitro ion fluxes measured under voltage clamp condition, and biochemical and molecular studies of enzyme activities, identified apical H+,K+-ATPase as the mediator of active K+ absorption in animal colon.
    3. Aldosterone-stimulated active K+ absorption in animal colon reflects enhanced apical H+,K+-ATPase mRNA expression and protein activity.
    4. Although apical H+,K+-ATPase mediates active K+ absorption in animal colon, the molecular basis for K+ absorption in human colon has yet to be identified.
  2. K+ secretion:
    1. Active K+ secretion occurs in both animal and human colon.
    2. Apical K+ channels and basolateral Na+-K+-2Cl- cotransport coordinate active K+ secretion.
    3. Ca2+-activated large conductance K+ (BK) channels constitute the main apical K+ conductance for K+ exit into the lumen.
  3. Role and regulation of active K+ secretion:
    1. Aldosterone and high-K+ diet stimulate apical BK channel expression and active K+ secretion.
    2. Upregulated BK channel expression is the adaptive mechanism for K+ secretion in patients with end-stage renal disease.
    3. Increased BK channel expression and K+ secretion likely contribute to diarrhea in patients with ulcerative colitis.
    4. Potassium channels could be a potential therapeutic target to control diarrhea in ulcerative colitis.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: Small intestine has a large capacity for K+ absorption. Humans normally consume 90 mEq K+/day. Small intestine is presented with dietary K+, and K+ within salivary, gastric, biliary, pancreatic and intestinal secretions. Since only 10 mEq K+/day passes from the small intestine into the colon, small intestine absorbs about 90 mEq K+/day. The colon (large intestine) is presented with K+ from the small intestine and that arising from colonic K+ secretion. The colon secretes 5 mEq K+/day and absorbs 5 mEq K+/day. As a result, 10 mEq K+/day is excreted in the feces. No active K+ absorptive mechanism has been identified in human small intestine, and thus K+ absorption may occur by solvent drag and/or be driven by membrane potential.

Figure 2 Teaching points: H+,K+-ATPase localized to the apical membranes has been shown to mediate active K+ absorption in animal (guinea pig, mouse, and rat) colon. H+,K+-ATPase-mediated electroneutral K+ absorption is partially Cl- dependent, but it is not known whether an anion exchanger (AE) linking Cl- absorption to HCO3- secretion is involved in K+ absorption. K+ absorbed across apical membranes exits across basolateral membranes via either K+ and Cl- channels operating in parallel, or K+-Cl- cotransport (KCC).

Figure 3 Teaching points: Active K+ absorption present in animal (guinea pig, mouse and rat) colon is partially inhibited by ouabain (Na+,K+-ATPase inhibitor), and therefore has both ouabain-sensitive and ouabain-insensitive components. Biochemical studies characterized ouabain-sensitive and ouabain-insensitive H+,K+-ATPase activities in animal colonic epithelial cells. Physiological studies monitoring the effect extracellular K+ on intracellular pH homeostasis in rat colon identified K+-dependent cellular pH homeostasis regulated by ouabain-sensitive and ouabain-insensitive H+,K+-ATPases localized to crypt cells (shown in red), and surface and upper third of crypt cells (shown in yellow), respectively. Both ouabain-sensitive and ouabain-insensitive H+,K+-ATPase are inhabited by vanadate (VO4, P-type ATPase inhibitor).

Figure 4 Teaching points: In rats, prolonged (7-10 days) feeding of a Na+-free diet increases circulating aldosterone levels. In rats fed a normal diet, large conductance K+ (BK) channels mediate active K+ secretion in the proximal colon, whereas H+,K+-ATPase mediates active K+ absorption in the distal colon (left panel). Aldosterone (induced by feeding a Na+-free diet) increases H+,K+-ATPase-mediated K+ absorption, and induces BK channel expression and BK channel-mediated K+ secretion in distal colon. It is not known whether aldosterone also stimulates BK channel-mediated K+ secretion in proximal colon.

Figure 5 Teaching points: Apical membrane K+ channels mediate active K+ secretion during pathological conditions of the colon, such as ulcerative colitis. Active K+ secretion requires the coordinated regulation of basolateral Na+-K+-2Cl- cotransporters (NKCC) and the Cl- channel-2 (CLC2), and apical BK channel. cAMP activates both NKCC and BK channels.

Figure 6 Teaching points: Under basal conditions, K+ exiting through basolateral K+ channels maintains Na+,K+-ATPase activity, thereby maintaining low intracellular Na+ and high intracellular K+ concentrations, and a negative intracellular electrical potential in colonic epithelial cells. This electrochemical gradient provides the driving force required for the secondary active Na+ absorption mediated by apical membrane Na+-H+ exchanger isoforms 2 and 3 (NHE2/NHE3) and epithelial Na+ channel (ENaC). NHE2 and NHE3 mediate electroneutral Na+ absorption, while ENaC mediates electrogenic Na+ absorption [A]. K+ exits through basolateral membrane intermediate conductance K+ (IK) channels, maintaining an intracellular K+ concentration that favors Na+-K+-2Cl- cotransporter (Cl- loader) function, which is required for continuous active Cl- secretion (e.g., during cholera infection) through apical membrane cystic fibrosis transmembrane regulator (CFTR) Cl- channels [B].

Figure 7 Teaching points: Increasing intracellular cAMP (by adding forskolin, FSK, an activator of adenylate cyclase) inhibits active (net) K+ absorption present under basal conditions in normal rat distal colon (A). Mucosal presence of vanadate (VO4; H+,K+-ATPase inhibitor) unmasks cAMP-stimulated K+ secretion (B). It is to be noted that mucosal VO4 also inhibits basal K+ absorption in normal colon (see Figure-11). cAMP does not inhibit H+,K+-ATPase, but activates K+ channels and stimulates active K+ secretion. Inhibition of net K+ absorption by cAMP is secondary to the stimulation of active K+ secretion.

Figure 8 Teaching points: Intermediate conductance K+ (IK) channel-like proteins are localized to both the apical and lateral membranes of normal rat and human colon. K+ exiting through IK channels provides the driving force for active Cl- secretion during secretory diarrhea (e.g., cholera).

Figure 9 Teaching points: Apical membrane-specific intermediate conductance K+ (IKC) channels, which lack a transmembrane domain, requires a β-subunit-like accessory (“chaperon”) protein for plasma membrane expression in Xenopus oocytes. In the absence of “chaperon,” IKC proteins are expressed only in the cytoplasm.

Figure 10 Teaching points: K+ secretion following activation of apical membrane intermediate conductance K+ (IK) channels is inhibited by TRAM-34 (IK channel specific blocker). IK channel-mediated K+ secretion is not inhabited by iberiotoxin (IbTX, BK channel specific blocker).

Figure 11 Teaching points: In normal rat distal colon, H+,K+-ATPase-mediated active K+ absorption is inhibited by mucosal VO4 (H+,K+-ATPase inhibitor). In aldosterone-treated rat distal colon, which exhibits active K+ secretion, inhibition of H+,K+-ATPase-mediated K+ absorption by VO4 further enhances K+ secretion.

Figure 12 Teaching points: Aldosterone induces large conductance K+ channel α subunit (BKα) specific mRNA abundance and active K+ secretion. The aldosterone-induced BKα abundance occurs at the transcription level.

Figure 13 Teaching points: cAMP and cAMP/Ca2+ stimulate both active Cl- and K+ secretion in normal colon. Inflammation abolishes both cAMP- and Ca2+-stimulated Cl- and K+ secretion, and also results in active K+ secretion.

 

 

 

 


Related Articles:

Ion Transport Across the Large Intestine
Mechanism of Fluid Transport by Epithelia
Principles of Membrane Transport
Physiology of Electrolyte Transport in the Gut: Implications for Disease

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Colonic Potassium Absorption and Secretion in Health and Disease
 

How to Cite

Vazhaikkurichi M. Rajendran, Geoffrey I. Sandle. Colonic Potassium Absorption and Secretion in Health and Disease. Compr Physiol 2018, 8: 1513-1536. doi: 10.1002/cphy.c170030