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Neuromodulation: Purinergic Signaling in Respiratory Control

Gregory D. Funk

10.1002/cphy.c120004

Source: Volume 3, Issue 1, January 2013

Published online: January 2013

Full Article on Wiley Online Library



Abstract

The main functions of the respiratory neural network are to produce a coordinated, efficient, rhythmic motor behavior and maintain homeostatic control over blood oxygen and CO2/pH levels. Purinergic (ATP) signaling features prominently in these homeostatic reflexes. The signaling actions of ATP are produced through its binding to a diversity of ionotropic P2X and metabotropic P2Y receptors. However, its net effect on neuronal and network excitability is determined by the interaction between the three limbs of a complex system comprising the signaling actions of ATP at P2Rs, the distribution of multiple ectonucleotidases that differentially metabolize ATP into ADP, AMP, and adenosine (ADO), and the signaling actions of ATP metabolites, especially ADP at P2YRs and ADO at P1Rs. Understanding the significance of purinergic signaling is further complicated by the fact that neurons, glia, and the vasculature differentially express P2 and P1Rs, and that both neurons and glia release ATP. This article reviews at cellular, synaptic, and network levels, current understanding and emerging concepts about the diverse roles played by this three‐part signaling system in: mediating the chemosensitivity of respiratory networks to hypoxia and CO2/pH; modulating the activity of rhythm generating networks and inspiratory motoneurons, and; controlling blood flow through the cerebral vasculature. © 2013 American Physiological Society. Compr Physiol 3:331‐363, 2013.

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Figure 1. Figure 1.

When ATP is released into the extracellular space, it acts via a three‐part signaling system comprising: (i) the actions of ATP (and ADP) at P2Rs; (ii) diverse ecto‐nucleotidases with differential substrate affinities that degrade ATP and its byproducts ultimately to adenosine (ADO); and, (iii) the actions of ADO at P1Rs. (Ecto 5′, ecto‐5′‐ectonucleotidase; ENPPs, ectonucleotide pyrophosphatase/phosphodiesterease; TNAP, tissue nonspecific alkaline phosphatase).
Figure 2. Figure 2.

Purinergic signaling has multiple roles in shaping the biphasic ventilatory response to hypoxia. (A) The hypoxic ventilatory response, shown here from anesthetized piglets (green) and adult pigs (blue) exposed to 6% inspired O2, is biphasic. It comprises an initial increase followed by a gradual decline, referred to as the secondary depression or “roll‐off.” Note that despite a similar initial increase (upward arrows), compare to adults (blue downward arrow), the roll‐off is more pronounced in neonates (green downward arrow) where ventilation falls below baseline (green shading) [Adapted, with permission, from reference (189)]. (B) In the carotid body, the P2X2 receptor subunit is a major contributor to the initial increase in ventilation that is evoked by hypoxia in mice. The graph shows respiratory responses (plotted as change in minute ventilation (E) from control) to varying levels of hypoxia in conscious wild‐type (blue) and P2X2‐deficient (green) mice. Adapted, with permission, from reference (222). (C and D) ATP released within the ventral respiratory column during hypoxia offsets the magnitude of the secondary respiratory depression. Traces in (C) illustrate changes in the arterial blood pressure (ABP), integrated phrenic nerve discharge (∫Phrenic), and null and ATP sensor currents (measured at the ventral medullary surface immediately ventral to the ventral respiratory column) during exposure to systemic hypoxia (10% O2 in the inspired air). Prior to hypoxia, rats were mechanically hyperventilated to induce central apnea (arterial PCO2 and end‐tidal CO2 below apneic threshold). Note that the release of ATP at the ventral surface of the medulla oblongata occurs after the initial increase in phrenic nerve activity. (D) P2 receptor blockade in the ventrolateral medulla augments the hypoxia‐induced secondary depression of ventilation in adult rats. Summary data show the effect of pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate (PPADS, P2 receptor antagonist) on changes in minute ventilation evoked by hypoxia. *Significant difference from control response, P < 0.05. Adapted, with permission, from reference (102). (E) During hypoxia, adenosine (ADO) contributes to the secondary depression of ventilation. Curves illustrate ventilatory responses of decerebrate rabbit pups to 6% O2 during saline infusion (control) or following infusion of ADO antagonists (aminophylline, 25 mg kg−1; or 8‐p‐sulfophenyltheophylline, 5 mg kg−1). Ventilation is expressed as percent of the prehypoxic level (% control). Adapted, with permission, from reference (227).
Figure 3. Figure 3.

Carotid body chemoreceptor function: location, purinergic signaling mechanisms and central projections. (A) The carotid bodies are located bilaterally in the neck at the bifurcation of the common carotid artery into the internal and external carotid arteries. (B) Enlarged view of the box in (A) showing the carotid body and its afferent innervation via the carotid sinus nerve. (C) Enlarged view of a cross‐section through the carotid body (at the blue line in B) showing arrangement of glomus cells (Type I cells; the sensors), sustentacular cells (Type II cells; glia‐like), capillaries and carotid sinus nerve and parasympathetic nerve endings (efferent axon). Signal transducation pathways for conversion of decreased O2 (lower Glomus cell [steps 1‐8]) increased CO2 (upper Glomus cell [steps i‐vii + 8]) and into transmitter release and action potential generation in carotid sinus nerve are depicted. Autocrine (step I) and paracrine (step II) actions of ATP and ADO (step 8) are also depicted. (D) Dorsal view of the medulla and pons showing central projections of carotid sinus nerve afferent fibers in the medulla. The first‐order excitatory synapse is in the nucleus tractus solitarius (NTS). These neurons project to the pontine respiratory group (PRG) and chemosensitive neurons in the parafacial respiratory group/retrofacial nucleus (pFRG/RTN) that in turn send excitatory projections to the pre‐BötC and possibly other regions of the ventral respiratory column. Note that while this diagram focuses on purinergic signaling in the carotid body, additional small molecule neurotransmitters and neuromodulators contribute to chemosensory processing in the rat carotid body.
Figure 4. Figure 4.

Proposed model of the three‐part ATP signaling system operating at the tripartite, glutamatergic inspiratory synapse (comprising pre‐ and postsynaptic neurons and astrocytes) in the ventral respiratory column and pre‐BötC. A volley of action potentials in presynaptic neuron during inspiration evokes glutamate (Glu) release (1), which excites the postsynaptic neuron via ionotropic (GluR) and metabotropic (mGluR) glutamate receptors. When ATP is released into the extracellular space (3), it directly activates P2Y1Rs on neurons (4) and glia (5). In glia, ATP evokes an increase in Ca2+ (6) (via mechanisms outlined in Figure 7), which leads to the exocytotic release of gliotransmitters ATP, glutamate (Glu) (7), and D‐serine (not shown). Glu indirectly excites the postsynaptic neuron through ionotropic (AMPA and NMDAR) or mGluRs (8) while ATP acts via P2Rs that couple through phospholipase C and protein kinase C (PKC) and modulate membrane ion channels (see Figure 7). ATP also acts in autocrine/paracrine manner to enhance gliotransmitter release (9). ATP is degraded by ectonucleotidases (10), producing ADP (which activates P2Y1Rs, not shown) and adenosine (ADO), which acts on presynaptic P1Rs to inhibit Glu release (11) and postsynaptic P1Rs (12), causing hyperpolarization via activation of KATP channels.
Figure 5. Figure 5.

The pre‐BötC and pre‐BötC respiratory neurons are sensitive to ATP. (A) Rhythmic XII nerve activity recorded from a rat medullary slice preparation showing a dramatic increase in burst frequency following local injection of ATP (100 μM, 10 s) or the nonhydrolyzable ATP analogue, ATPγS (100 μM, 10 s) into the pre‐BötC. (B) Current‐clamp recording from a respiratory neuron displaying voltage‐dependent bursting behavior. In the top trace of membrane potential (VM), bursts occur at the same frequency as the XII nerve (∫XII). Spontaneous burst frequency increases when cell is depolarized from −65 to −60 and −55 mV. C. This neuron responded to local application of the P2YR agonist, 2MeSADP (1 mM), with an inward current (IM = membrane current) or depolarization. (D) Whole‐cell recording from a nonpacemaker respiratory neuron that responds to ATP and 2MeSADP with an inward current or depolarization. (A) Adapted, with permission, from reference (166) (B‐D) from reference (167)).
Figure 6. Figure 6.

Glia contribute to the increase in inspiratory‐related frequency evoked by ATP in the pre‐BötC in vitro. Rhythmic inspiratory‐related activity recorded as integrated XII nerve activity (∫XII) from a rat medullary slice illustrates frequency increases evoked by local application of ATP (0.1 mM, 10 s, A) and SP (1 μM, 10 s, B) into the pre‐BötC during control conditions (left panels) and after disruption of rhythm by bath application (1‐2 h) of the glial toxin [methionine sulfoxamine (MSO, 0.1 mM)] and the subsequent restoration of rhythm by bath application of glutamine (GLN, 1.5 mM, middle panels] (n = 7). (*Significant difference between ATP responses, P < 0.001. Adapted, with permission, from reference (124).
Figure 7. Figure 7.

Signaling cascades through which ATP is hypothesized to affect astrocytes and subsequently neuronal excitability. Extracellular ATP activates astrocytic P2Y, including P2Y1, receptors (1), activating the Gαq/11 second messenger cascade (2) which acts through PLC, PIP2 and IP3 (3) to evoke the release of Ca2+ from intracellular stores (4). Increased Ca2+ triggers exocytotic release of ATP, glutamate, and D‐serine (5). Astrocytic ATP can act in an autocrine/paracrine manner on other astrocytes to evoke further transmitter release (ATP‐evoked ATP release) and propagate Ca2+ waves through local glial networks (6). ATP is also hypothesized to excite local neurons, in part via P2Y1Rs (7) and the Gαq/11 second messenger pathway (10), which, via activation of PKC (11,12,13,14), modulates membrane ion channels including ICAN (15) to increase excitability. Astrocytic glutamate will act in an autocrine/ paracrine manner on astrocytes via mGluRs (not shown) and increase neuronal excitability through activation of glutamate receptors (mGluRs, AMPA, NMDA) (8). Astrocytic D‐serine, a positive allosteric modulator of the NMDA subtype of glutamate receptor, may also increase excitability by potentiating NMDA currents (9). Abbreviations: DAG, diacyl‐glycerol; ER, endoplasmic reticulum; Glu, glutamate; IP3, inositol trisphosposphate; mGluR, metabotropic glutamate receptor; PIP2, phosphatidylinositol 4,5‐bisphosphate; PKC, protein kinase C; PLC, phospholipase C; R, receptor).
Figure 8. Figure 8.

Local application of ATP into the pre‐BötC evokes a frequency response that closely follows the ATP concentration profile. (A) Schematic of the experimental setup showing the rhythmic medullary slice, triple‐barrel drug pipette for pressure injecting drugs (ATP) and the ATP and null sensors, all placed within the pre‐BötC. ATP (100 μ, 10 s) is injected into the pre‐BötC (site 1) and the ATP concentration within the pre‐BotC (difference current between null and ATP sensor currents) and inspiratory frequency are monitored (recorded from the XII nerve via a suction electrode). The drug injection pipette is then moved away from the pre‐BötC to site 2 (140 μm from site 1). (B) Trace of integrated XII nerve activity (∫XII) showing the rapid frequency response evoked by ATP in site 1. (C) Plots showing (for the same medullary slice preparation shown in B) the effects of locally applying ATP within the pre‐BötC (starting at t = 0) on inspiratory frequency (blue trace) and the ATP difference current (ATP sensor current‐null sensor current) within the pre‐BötC (green). (D) Inspiratory frequency and ATP difference current recorded in response to locally applying ATP at site 2. This more distant injection produces a different ATP concentration profile within the pre‐BötC, and, importantly, the frequency response still follows the ATP concentration profile measured within the pre‐BötC. Adapted, with permission, from reference (125).
Figure 9. Figure 9.

Differential purinergic modulation of pre‐BötC rhythm in rhythmic medullary slice preparations from mouse and rat. (A) P2Y1R activation in the pre‐BötC increases frequency in mouse and rat. Integrated XII nerve (∫XII) recordings showing responses to local application of the P2Y1R agonist MRS 2365 (0.1 mM, 10 s) in the pre‐BötC of rat and mouse. (B) Differential effects of ATP on pre‐BötC rhythm in mouse and rat. ∫XII recordings showing responses to local application of and ATP (0.1 mM, 10 s) in the pre‐BötC of rat and mouse. (C) DPCPX (an A1 ADOR antagonist) in the pre‐BötC of mouse unmasks an ATP‐mediated frequency increase. ∫XII recordings showing responses to local application of ATP (0.1 mM, 10 s; left trace) under control conditions and after a 90 s preapplication of an A1R antagonist (2 μM DPCPX; right trace). (D) Real‐time polymerase chain reaction analysis reveals differential expression of ectonucleotidase isoforms in tissue punches from mouse and rat. The percentage contribution of each ectonucleotidase isoform to the total ectonucleotidase mRNA expressed in pre‐BötC punches from rat (n = 4) and mouse (n = 6). Error bars indicate SEM. co.# indicates copy number. *Significant difference between the compared columns. Adapted, with permission, from reference (284).
Figure 10. Figure 10.

ATP released at the ventral medullary surface contributes to the hypercapnic ventilatory response via a P2R mechanism. (A) Rapid CO2‐induced release of ATP from the ventral surface of the medulla. An increase in the level of inspired CO2 in an adult anesthetized rat that had been hyperventilated to depress respiratory activity. Traces show changes in ATP and null sensor currents, respiratory activity (integrated phrenic nerve discharge, ∫phrenic) and respiratory frequency (fR) and end‐tidal CO2. The “Net ATP” trace represents the difference in signal between ATP and null sensors. (B) Expanded portion of A illustrating that ATP release precedes (arrow) respiratory activation. (C) Placement of sensors on the ventral surface of the medulla (py, pyramidal tract). The sensor surface is the entire platinum wire in contact with the ventral surface. Subsequent studies used small circular sensors to define ATP release sites along the ventral medullary surface (101). (D) ATP receptor blockade on the chemosensitive areas of the ventral medullary surface attenuates the effect of CO2 on breathing in rats. Sequential recordings illustrating the effect of increasing concentrations of the P2 antagonist pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate (PPADS) on the threshold level of end‐tidal CO2 level required to induce respiratory activity from hypocapnic apnoea. (E) Summary data (mean ± standard error) showing the increase in threshold levels of end‐tidal CO2 required to induce breathing from apnoea in the presence of PPADS (white columns; n = 8) or TNP‐ATP (black columns; n = 7) on the ventral medullary surface. * indicates significant difference, P < 0.05. Adapted, with permission, from reference (101).
Figure 11. Figure 11.

Optogenetic stimulation of channel Rhodopsin 2‐expressing astrocytes on the ventral medullary surface activated phox2b positive chemoreceptor neurons via an ATP‐dependent mechanism and triggered robust respiratory responses in vivo (C). (A) Ventral medullary astrocytes visualized by Case12 fluorescence. Adenovirus containing the gene for Case12 (a genetically encoded Ca2+ indicator) under the control of a glial specific promotor was injected into the ventral medullary surface of rats and tissue examined 7 to 10 days later. Left, arrows point at glia limitans. Right, penetrating arteriole enwrapped by astrocyte processes expressing Case12. Coronal brainstem sections (50 μm) from two individual rats (100). (B) Membrane potential of a phox2b positive retrotrapezoid nucleus (RTN) neuron illustrating its responses to light activation of adjacent ChR2(H134R)‐expressing astrocytes in the absence (left), presence (middle), or after washout (right) of MRS2179. Adapted, with permission, from reference (100). (C) Time‐condensed record from an anesthetized rat illustrating effects of repeated stimulations of ventral medullary surface astrocytes on phrenic nerve activity before and after a single application of MRS2179 (100 μM, 20 μL) on the ventral surface. Spontaneous recovery of the response over time can be seen. The rat is apneic (not breathing) in the absence of photostimulation because it is experiencing hypocapnic apnea, which was induced by means of mechanical hyperventilation to reduce arterial levels of PCO2/[H+] below the apneic threshold. IPNA, integrated phrenic nerve activity; TP, tracheal pressure; ABP, arterial blood pressure, RR, respiratory rate. Adapted, with permission, from reference (100).
Figure 12. Figure 12.

pH sensitivity of phox2b‐expressing chemosensitive retrotrapezoid nucleus (RTN) neurons in organotypic culture from 8‐ to 10‐day‐old rats is dependent on P2R signaling. (A) (Left) Image of the ventral aspect of an organotypic brainstem slice showing EGFP‐labeled Phox2b‐expressing RTN neurons, one of which is patch clamped. (Right) Time‐condensed record of the membrane potential of an RTN neuron responding to acidification in the absence and presence of the P2R antagonist, MRS2179. AP, action potentials (truncated); R, resistance tests using current pulses. (B) Summary of MRS2179 effect on pH‐evoked depolarizations in phox2b‐expressing RTN neurons. (C) (Left) Effect of MRS2179 on acidification‐induced intracellular Ca2+ response of an RTN neuron (ratiometric imaging using TN‐XXL, a genetically encoded Ca2+ indicator). (Right) RTN neurons expressing TN‐XXL under PRSx8 promotor control. (D) Summary data showing significant effect of MRS2179 on pH‐evoked intracellular Ca2+ responses of RTN neurons. Adapted, with permission, from reference (100).
Figure 13. Figure 13.

Chemosensory retrotrapezoid nucleus (RTN) neurons (i.e., phox2b neurons) in acute slices from 7‐ to 12‐day‐old rats are sensitive to ATP but their pH sensitivity is not dependent on ATP signaling. (A) Firing rate plot illustrating the excitatory effect of local pressure application of UTP (uridine triphosphate 1 mM, P2YR agonist) in a representative pH‐sensitive RTN neuron; the UTP‐evoked increase in firing was unaffected by block of ionotropic glutamate receptors with CNQX and APV (10 and 50 μM). B, In a different pH‐sensitive RTN neuron, the UTP‐stimulated firing was blocked by the P2R antagonist reactive blue 2 (RB2, 50 μM), but pH sensitivity was retained. (C) P2 receptors do not mediate pH sensitivity in RTN chemoreceptors. Summary data illustrating averaged (±SEM) firing rate at normal pH (7.3) and during bath acidification (pH 6.9) and alkalization (pH 7.5), under control conditions and in the presence of the P2 receptor antagonists PPADS (100 μM, n = 4) or RB2 (20‐50 μM, n = 10). There was no difference in pH sensitivity before or during P2R blockade; that is, the slope of the relationship between firing rate and bath pH was similar in control and following block of P2Rs. (Note: the chemosensory RTN neurons in this study were not identified as phox2b neurons but their behavior is entirely consistent with previously identified phox2b labeled, chemosensory RTN neurons). Adapted, with permission, from reference (191).
Figure 14. Figure 14.

Schematic of P2R signaling and its contribution to central chemosensitivity in the retrotrapezoid nucleus (RTN). Elevated CO2 in the blood diffuses across the blood vessel/capillary wall, increasing CO2 and H+ in the extracellular space surrounding neurons and astrocytes (1). Astrocytes near the ventral medullary surface including those in the glia limitans respond in two ways. Depicted in the middle astrocyte, elevated CO2 (intracellular or extracellular) evokes release of ATP through CO2‐sensitive Cx26 hemichannels (i.e., Cx26 hemichannels act as the CO2 sensor) (2). Depicted in the right astrocyte, CO2 or H+ also cause the release of intracellular Ca2+ (3) and Ca2+‐dependent, exocytotic release of ATP (4). ATP released via one or both of these mechanisms excites chemosensitive RTN neurons through a P2Y (5), G‐protein coupled receptor‐dependent mechanism that either modulates an unknown membrane conductance (6) or acid‐sensitive ion channels directly (7). RTN neurons are also directly sensitive to intra‐ or extracellular acidification; the H+ sensor may be a K+ channel that is open at rest and closes in response to increased H+ (8). Note, however, that while closure of a K+ channel is strongly implicated in the depolarization of RTN neurons by acid, there is no direct evidence that the depolarization is produced by the direct action of acid or CO2 on the K+ channel. Increased output from the RTN to the ventral respiratory column (VRC) including the pre‐BötC (9) causes ventilation to increase. The ATP‐dependent excitatory processes mediate approximately 25% of the central chemosensory response. The remainder of the response reflects direct activation of RTN and other chemosensory neurons. Additional actions of extracellular ATP appear to include a P2XR‐mediated, presynaptic excitation of inhibitory GABAergic inputs to RTN neurons (10) (the factors determining the balance to excitatory P2Y and indirect inhibitory P2XR mechanisms are not known) and an autocrine/paracrine P2YR‐mediated excitation of astrocytes (11). ATP also has complex actions on the vasculature. Under conditions of normal oxygenation in other brain regions, ATP causes the contraction of vascular smooth muscle (12) as well pericytes (13). The resultant reduction in blood flow is hypothesized to increase the CO2/pH stimulus and increase the response of local neurons/astrocytes. However, under conditions of reduced oxygen (hypoxia), there is growing evidence that the effects of ATP on both smooth muscle and pericytes reverses and facilitates restoration of blood flow to the hypoxic tissue. Whether the hypoxia‐dependent effects of ATP on the vasculature influence CO2/pH sensitivity of any respiratory chemosensory structure remains to be established.
Figure 15. Figure 15.

Effects of exogenously applied ATP on inspiratory motor output are biphasic. (A) Response of integrated C4 nerve root activity (∫C4) to application of ATP (10 mM, 60 s) over the C4 spinal cord (with pia removed) of a brainstem‐spinal cord preparation. (B) Time course of changes in ∫C4 inspiratory burst amplitude produced by 60 s local applications of 10 mM ATP (triangles) or 10 mM ATPγS (an hydrolysis‐resistant ATP analogue, closed circles) to the phrenic motoneuron column (n=5). Adapted with permission from (179). (C) Response of integrated XII nerve root activity (∫XII) to application of ATP (1.0 mM, 30 s) into the XII nucleus of the medullary slice preparation. (D) Time course of the changes in ∫XII inspiratory burst amplitude evoked by local application of ATP (1 mM) before (open circles) and during, (triangles) local application of theophylline (100 μM; n = 8). Adapted, with permission, from reference (87); values are means ± SE. * indicates significant difference from values at the same time during the control ATP application.


Figure 1.

When ATP is released into the extracellular space, it acts via a three‐part signaling system comprising: (i) the actions of ATP (and ADP) at P2Rs; (ii) diverse ecto‐nucleotidases with differential substrate affinities that degrade ATP and its byproducts ultimately to adenosine (ADO); and, (iii) the actions of ADO at P1Rs. (Ecto 5′, ecto‐5′‐ectonucleotidase; ENPPs, ectonucleotide pyrophosphatase/phosphodiesterease; TNAP, tissue nonspecific alkaline phosphatase).



Figure 2.

Purinergic signaling has multiple roles in shaping the biphasic ventilatory response to hypoxia. (A) The hypoxic ventilatory response, shown here from anesthetized piglets (green) and adult pigs (blue) exposed to 6% inspired O2, is biphasic. It comprises an initial increase followed by a gradual decline, referred to as the secondary depression or “roll‐off.” Note that despite a similar initial increase (upward arrows), compare to adults (blue downward arrow), the roll‐off is more pronounced in neonates (green downward arrow) where ventilation falls below baseline (green shading) [Adapted, with permission, from reference (189)]. (B) In the carotid body, the P2X2 receptor subunit is a major contributor to the initial increase in ventilation that is evoked by hypoxia in mice. The graph shows respiratory responses (plotted as change in minute ventilation (E) from control) to varying levels of hypoxia in conscious wild‐type (blue) and P2X2‐deficient (green) mice. Adapted, with permission, from reference (222). (C and D) ATP released within the ventral respiratory column during hypoxia offsets the magnitude of the secondary respiratory depression. Traces in (C) illustrate changes in the arterial blood pressure (ABP), integrated phrenic nerve discharge (∫Phrenic), and null and ATP sensor currents (measured at the ventral medullary surface immediately ventral to the ventral respiratory column) during exposure to systemic hypoxia (10% O2 in the inspired air). Prior to hypoxia, rats were mechanically hyperventilated to induce central apnea (arterial PCO2 and end‐tidal CO2 below apneic threshold). Note that the release of ATP at the ventral surface of the medulla oblongata occurs after the initial increase in phrenic nerve activity. (D) P2 receptor blockade in the ventrolateral medulla augments the hypoxia‐induced secondary depression of ventilation in adult rats. Summary data show the effect of pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate (PPADS, P2 receptor antagonist) on changes in minute ventilation evoked by hypoxia. *Significant difference from control response, P < 0.05. Adapted, with permission, from reference (102). (E) During hypoxia, adenosine (ADO) contributes to the secondary depression of ventilation. Curves illustrate ventilatory responses of decerebrate rabbit pups to 6% O2 during saline infusion (control) or following infusion of ADO antagonists (aminophylline, 25 mg kg−1; or 8‐p‐sulfophenyltheophylline, 5 mg kg−1). Ventilation is expressed as percent of the prehypoxic level (% control). Adapted, with permission, from reference (227).



Figure 3.

Carotid body chemoreceptor function: location, purinergic signaling mechanisms and central projections. (A) The carotid bodies are located bilaterally in the neck at the bifurcation of the common carotid artery into the internal and external carotid arteries. (B) Enlarged view of the box in (A) showing the carotid body and its afferent innervation via the carotid sinus nerve. (C) Enlarged view of a cross‐section through the carotid body (at the blue line in B) showing arrangement of glomus cells (Type I cells; the sensors), sustentacular cells (Type II cells; glia‐like), capillaries and carotid sinus nerve and parasympathetic nerve endings (efferent axon). Signal transducation pathways for conversion of decreased O2 (lower Glomus cell [steps 1‐8]) increased CO2 (upper Glomus cell [steps i‐vii + 8]) and into transmitter release and action potential generation in carotid sinus nerve are depicted. Autocrine (step I) and paracrine (step II) actions of ATP and ADO (step 8) are also depicted. (D) Dorsal view of the medulla and pons showing central projections of carotid sinus nerve afferent fibers in the medulla. The first‐order excitatory synapse is in the nucleus tractus solitarius (NTS). These neurons project to the pontine respiratory group (PRG) and chemosensitive neurons in the parafacial respiratory group/retrofacial nucleus (pFRG/RTN) that in turn send excitatory projections to the pre‐BötC and possibly other regions of the ventral respiratory column. Note that while this diagram focuses on purinergic signaling in the carotid body, additional small molecule neurotransmitters and neuromodulators contribute to chemosensory processing in the rat carotid body.



Figure 4.

Proposed model of the three‐part ATP signaling system operating at the tripartite, glutamatergic inspiratory synapse (comprising pre‐ and postsynaptic neurons and astrocytes) in the ventral respiratory column and pre‐BötC. A volley of action potentials in presynaptic neuron during inspiration evokes glutamate (Glu) release (1), which excites the postsynaptic neuron via ionotropic (GluR) and metabotropic (mGluR) glutamate receptors. When ATP is released into the extracellular space (3), it directly activates P2Y1Rs on neurons (4) and glia (5). In glia, ATP evokes an increase in Ca2+ (6) (via mechanisms outlined in Figure 7), which leads to the exocytotic release of gliotransmitters ATP, glutamate (Glu) (7), and D‐serine (not shown). Glu indirectly excites the postsynaptic neuron through ionotropic (AMPA and NMDAR) or mGluRs (8) while ATP acts via P2Rs that couple through phospholipase C and protein kinase C (PKC) and modulate membrane ion channels (see Figure 7). ATP also acts in autocrine/paracrine manner to enhance gliotransmitter release (9). ATP is degraded by ectonucleotidases (10), producing ADP (which activates P2Y1Rs, not shown) and adenosine (ADO), which acts on presynaptic P1Rs to inhibit Glu release (11) and postsynaptic P1Rs (12), causing hyperpolarization via activation of KATP channels.



Figure 5.

The pre‐BötC and pre‐BötC respiratory neurons are sensitive to ATP. (A) Rhythmic XII nerve activity recorded from a rat medullary slice preparation showing a dramatic increase in burst frequency following local injection of ATP (100 μM, 10 s) or the nonhydrolyzable ATP analogue, ATPγS (100 μM, 10 s) into the pre‐BötC. (B) Current‐clamp recording from a respiratory neuron displaying voltage‐dependent bursting behavior. In the top trace of membrane potential (VM), bursts occur at the same frequency as the XII nerve (∫XII). Spontaneous burst frequency increases when cell is depolarized from −65 to −60 and −55 mV. C. This neuron responded to local application of the P2YR agonist, 2MeSADP (1 mM), with an inward current (IM = membrane current) or depolarization. (D) Whole‐cell recording from a nonpacemaker respiratory neuron that responds to ATP and 2MeSADP with an inward current or depolarization. (A) Adapted, with permission, from reference (166) (B‐D) from reference (167)).



Figure 6.

Glia contribute to the increase in inspiratory‐related frequency evoked by ATP in the pre‐BötC in vitro. Rhythmic inspiratory‐related activity recorded as integrated XII nerve activity (∫XII) from a rat medullary slice illustrates frequency increases evoked by local application of ATP (0.1 mM, 10 s, A) and SP (1 μM, 10 s, B) into the pre‐BötC during control conditions (left panels) and after disruption of rhythm by bath application (1‐2 h) of the glial toxin [methionine sulfoxamine (MSO, 0.1 mM)] and the subsequent restoration of rhythm by bath application of glutamine (GLN, 1.5 mM, middle panels] (n = 7). (*Significant difference between ATP responses, P < 0.001. Adapted, with permission, from reference (124).



Figure 7.

Signaling cascades through which ATP is hypothesized to affect astrocytes and subsequently neuronal excitability. Extracellular ATP activates astrocytic P2Y, including P2Y1, receptors (1), activating the Gαq/11 second messenger cascade (2) which acts through PLC, PIP2 and IP3 (3) to evoke the release of Ca2+ from intracellular stores (4). Increased Ca2+ triggers exocytotic release of ATP, glutamate, and D‐serine (5). Astrocytic ATP can act in an autocrine/paracrine manner on other astrocytes to evoke further transmitter release (ATP‐evoked ATP release) and propagate Ca2+ waves through local glial networks (6). ATP is also hypothesized to excite local neurons, in part via P2Y1Rs (7) and the Gαq/11 second messenger pathway (10), which, via activation of PKC (11,12,13,14), modulates membrane ion channels including ICAN (15) to increase excitability. Astrocytic glutamate will act in an autocrine/ paracrine manner on astrocytes via mGluRs (not shown) and increase neuronal excitability through activation of glutamate receptors (mGluRs, AMPA, NMDA) (8). Astrocytic D‐serine, a positive allosteric modulator of the NMDA subtype of glutamate receptor, may also increase excitability by potentiating NMDA currents (9). Abbreviations: DAG, diacyl‐glycerol; ER, endoplasmic reticulum; Glu, glutamate; IP3, inositol trisphosposphate; mGluR, metabotropic glutamate receptor; PIP2, phosphatidylinositol 4,5‐bisphosphate; PKC, protein kinase C; PLC, phospholipase C; R, receptor).



Figure 8.

Local application of ATP into the pre‐BötC evokes a frequency response that closely follows the ATP concentration profile. (A) Schematic of the experimental setup showing the rhythmic medullary slice, triple‐barrel drug pipette for pressure injecting drugs (ATP) and the ATP and null sensors, all placed within the pre‐BötC. ATP (100 μ, 10 s) is injected into the pre‐BötC (site 1) and the ATP concentration within the pre‐BotC (difference current between null and ATP sensor currents) and inspiratory frequency are monitored (recorded from the XII nerve via a suction electrode). The drug injection pipette is then moved away from the pre‐BötC to site 2 (140 μm from site 1). (B) Trace of integrated XII nerve activity (∫XII) showing the rapid frequency response evoked by ATP in site 1. (C) Plots showing (for the same medullary slice preparation shown in B) the effects of locally applying ATP within the pre‐BötC (starting at t = 0) on inspiratory frequency (blue trace) and the ATP difference current (ATP sensor current‐null sensor current) within the pre‐BötC (green). (D) Inspiratory frequency and ATP difference current recorded in response to locally applying ATP at site 2. This more distant injection produces a different ATP concentration profile within the pre‐BötC, and, importantly, the frequency response still follows the ATP concentration profile measured within the pre‐BötC. Adapted, with permission, from reference (125).



Figure 9.

Differential purinergic modulation of pre‐BötC rhythm in rhythmic medullary slice preparations from mouse and rat. (A) P2Y1R activation in the pre‐BötC increases frequency in mouse and rat. Integrated XII nerve (∫XII) recordings showing responses to local application of the P2Y1R agonist MRS 2365 (0.1 mM, 10 s) in the pre‐BötC of rat and mouse. (B) Differential effects of ATP on pre‐BötC rhythm in mouse and rat. ∫XII recordings showing responses to local application of and ATP (0.1 mM, 10 s) in the pre‐BötC of rat and mouse. (C) DPCPX (an A1 ADOR antagonist) in the pre‐BötC of mouse unmasks an ATP‐mediated frequency increase. ∫XII recordings showing responses to local application of ATP (0.1 mM, 10 s; left trace) under control conditions and after a 90 s preapplication of an A1R antagonist (2 μM DPCPX; right trace). (D) Real‐time polymerase chain reaction analysis reveals differential expression of ectonucleotidase isoforms in tissue punches from mouse and rat. The percentage contribution of each ectonucleotidase isoform to the total ectonucleotidase mRNA expressed in pre‐BötC punches from rat (n = 4) and mouse (n = 6). Error bars indicate SEM. co.# indicates copy number. *Significant difference between the compared columns. Adapted, with permission, from reference (284).



Figure 10.

ATP released at the ventral medullary surface contributes to the hypercapnic ventilatory response via a P2R mechanism. (A) Rapid CO2‐induced release of ATP from the ventral surface of the medulla. An increase in the level of inspired CO2 in an adult anesthetized rat that had been hyperventilated to depress respiratory activity. Traces show changes in ATP and null sensor currents, respiratory activity (integrated phrenic nerve discharge, ∫phrenic) and respiratory frequency (fR) and end‐tidal CO2. The “Net ATP” trace represents the difference in signal between ATP and null sensors. (B) Expanded portion of A illustrating that ATP release precedes (arrow) respiratory activation. (C) Placement of sensors on the ventral surface of the medulla (py, pyramidal tract). The sensor surface is the entire platinum wire in contact with the ventral surface. Subsequent studies used small circular sensors to define ATP release sites along the ventral medullary surface (101). (D) ATP receptor blockade on the chemosensitive areas of the ventral medullary surface attenuates the effect of CO2 on breathing in rats. Sequential recordings illustrating the effect of increasing concentrations of the P2 antagonist pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate (PPADS) on the threshold level of end‐tidal CO2 level required to induce respiratory activity from hypocapnic apnoea. (E) Summary data (mean ± standard error) showing the increase in threshold levels of end‐tidal CO2 required to induce breathing from apnoea in the presence of PPADS (white columns; n = 8) or TNP‐ATP (black columns; n = 7) on the ventral medullary surface. * indicates significant difference, P < 0.05. Adapted, with permission, from reference (101).



Figure 11.

Optogenetic stimulation of channel Rhodopsin 2‐expressing astrocytes on the ventral medullary surface activated phox2b positive chemoreceptor neurons via an ATP‐dependent mechanism and triggered robust respiratory responses in vivo (C). (A) Ventral medullary astrocytes visualized by Case12 fluorescence. Adenovirus containing the gene for Case12 (a genetically encoded Ca2+ indicator) under the control of a glial specific promotor was injected into the ventral medullary surface of rats and tissue examined 7 to 10 days later. Left, arrows point at glia limitans. Right, penetrating arteriole enwrapped by astrocyte processes expressing Case12. Coronal brainstem sections (50 μm) from two individual rats (100). (B) Membrane potential of a phox2b positive retrotrapezoid nucleus (RTN) neuron illustrating its responses to light activation of adjacent ChR2(H134R)‐expressing astrocytes in the absence (left), presence (middle), or after washout (right) of MRS2179. Adapted, with permission, from reference (100). (C) Time‐condensed record from an anesthetized rat illustrating effects of repeated stimulations of ventral medullary surface astrocytes on phrenic nerve activity before and after a single application of MRS2179 (100 μM, 20 μL) on the ventral surface. Spontaneous recovery of the response over time can be seen. The rat is apneic (not breathing) in the absence of photostimulation because it is experiencing hypocapnic apnea, which was induced by means of mechanical hyperventilation to reduce arterial levels of PCO2/[H+] below the apneic threshold. IPNA, integrated phrenic nerve activity; TP, tracheal pressure; ABP, arterial blood pressure, RR, respiratory rate. Adapted, with permission, from reference (100).



Figure 12.

pH sensitivity of phox2b‐expressing chemosensitive retrotrapezoid nucleus (RTN) neurons in organotypic culture from 8‐ to 10‐day‐old rats is dependent on P2R signaling. (A) (Left) Image of the ventral aspect of an organotypic brainstem slice showing EGFP‐labeled Phox2b‐expressing RTN neurons, one of which is patch clamped. (Right) Time‐condensed record of the membrane potential of an RTN neuron responding to acidification in the absence and presence of the P2R antagonist, MRS2179. AP, action potentials (truncated); R, resistance tests using current pulses. (B) Summary of MRS2179 effect on pH‐evoked depolarizations in phox2b‐expressing RTN neurons. (C) (Left) Effect of MRS2179 on acidification‐induced intracellular Ca2+ response of an RTN neuron (ratiometric imaging using TN‐XXL, a genetically encoded Ca2+ indicator). (Right) RTN neurons expressing TN‐XXL under PRSx8 promotor control. (D) Summary data showing significant effect of MRS2179 on pH‐evoked intracellular Ca2+ responses of RTN neurons. Adapted, with permission, from reference (100).



Figure 13.

Chemosensory retrotrapezoid nucleus (RTN) neurons (i.e., phox2b neurons) in acute slices from 7‐ to 12‐day‐old rats are sensitive to ATP but their pH sensitivity is not dependent on ATP signaling. (A) Firing rate plot illustrating the excitatory effect of local pressure application of UTP (uridine triphosphate 1 mM, P2YR agonist) in a representative pH‐sensitive RTN neuron; the UTP‐evoked increase in firing was unaffected by block of ionotropic glutamate receptors with CNQX and APV (10 and 50 μM). B, In a different pH‐sensitive RTN neuron, the UTP‐stimulated firing was blocked by the P2R antagonist reactive blue 2 (RB2, 50 μM), but pH sensitivity was retained. (C) P2 receptors do not mediate pH sensitivity in RTN chemoreceptors. Summary data illustrating averaged (±SEM) firing rate at normal pH (7.3) and during bath acidification (pH 6.9) and alkalization (pH 7.5), under control conditions and in the presence of the P2 receptor antagonists PPADS (100 μM, n = 4) or RB2 (20‐50 μM, n = 10). There was no difference in pH sensitivity before or during P2R blockade; that is, the slope of the relationship between firing rate and bath pH was similar in control and following block of P2Rs. (Note: the chemosensory RTN neurons in this study were not identified as phox2b neurons but their behavior is entirely consistent with previously identified phox2b labeled, chemosensory RTN neurons). Adapted, with permission, from reference (191).



Figure 14.

Schematic of P2R signaling and its contribution to central chemosensitivity in the retrotrapezoid nucleus (RTN). Elevated CO2 in the blood diffuses across the blood vessel/capillary wall, increasing CO2 and H+ in the extracellular space surrounding neurons and astrocytes (1). Astrocytes near the ventral medullary surface including those in the glia limitans respond in two ways. Depicted in the middle astrocyte, elevated CO2 (intracellular or extracellular) evokes release of ATP through CO2‐sensitive Cx26 hemichannels (i.e., Cx26 hemichannels act as the CO2 sensor) (2). Depicted in the right astrocyte, CO2 or H+ also cause the release of intracellular Ca2+ (3) and Ca2+‐dependent, exocytotic release of ATP (4). ATP released via one or both of these mechanisms excites chemosensitive RTN neurons through a P2Y (5), G‐protein coupled receptor‐dependent mechanism that either modulates an unknown membrane conductance (6) or acid‐sensitive ion channels directly (7). RTN neurons are also directly sensitive to intra‐ or extracellular acidification; the H+ sensor may be a K+ channel that is open at rest and closes in response to increased H+ (8). Note, however, that while closure of a K+ channel is strongly implicated in the depolarization of RTN neurons by acid, there is no direct evidence that the depolarization is produced by the direct action of acid or CO2 on the K+ channel. Increased output from the RTN to the ventral respiratory column (VRC) including the pre‐BötC (9) causes ventilation to increase. The ATP‐dependent excitatory processes mediate approximately 25% of the central chemosensory response. The remainder of the response reflects direct activation of RTN and other chemosensory neurons. Additional actions of extracellular ATP appear to include a P2XR‐mediated, presynaptic excitation of inhibitory GABAergic inputs to RTN neurons (10) (the factors determining the balance to excitatory P2Y and indirect inhibitory P2XR mechanisms are not known) and an autocrine/paracrine P2YR‐mediated excitation of astrocytes (11). ATP also has complex actions on the vasculature. Under conditions of normal oxygenation in other brain regions, ATP causes the contraction of vascular smooth muscle (12) as well pericytes (13). The resultant reduction in blood flow is hypothesized to increase the CO2/pH stimulus and increase the response of local neurons/astrocytes. However, under conditions of reduced oxygen (hypoxia), there is growing evidence that the effects of ATP on both smooth muscle and pericytes reverses and facilitates restoration of blood flow to the hypoxic tissue. Whether the hypoxia‐dependent effects of ATP on the vasculature influence CO2/pH sensitivity of any respiratory chemosensory structure remains to be established.



Figure 15.

Effects of exogenously applied ATP on inspiratory motor output are biphasic. (A) Response of integrated C4 nerve root activity (∫C4) to application of ATP (10 mM, 60 s) over the C4 spinal cord (with pia removed) of a brainstem‐spinal cord preparation. (B) Time course of changes in ∫C4 inspiratory burst amplitude produced by 60 s local applications of 10 mM ATP (triangles) or 10 mM ATPγS (an hydrolysis‐resistant ATP analogue, closed circles) to the phrenic motoneuron column (n=5). Adapted with permission from (179). (C) Response of integrated XII nerve root activity (∫XII) to application of ATP (1.0 mM, 30 s) into the XII nucleus of the medullary slice preparation. (D) Time course of the changes in ∫XII inspiratory burst amplitude evoked by local application of ATP (1 mM) before (open circles) and during, (triangles) local application of theophylline (100 μM; n = 8). Adapted, with permission, from reference (87); values are means ± SE. * indicates significant difference from values at the same time during the control ATP application.

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Article Title: Neuromodulation: Purinergic Signaling in Respiratory Control
 

How to Cite

Gregory D. Funk. Neuromodulation: Purinergic Signaling in Respiratory Control. Compr Physiol 2013, 3: 331-363. doi: 10.1002/cphy.c120004