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Liver Receptors for Regulatory Peptides

Gabriel Rosselin

10.1002/cphy.cp060212

Source: Supplement 17: Handbook of Physiology, The Gastrointestinal System, Neural and Endocrine Biology

Originally published: 1989

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Methodology of Receptor Studies in Liver
1.1 Receptor‐Binding Assay
1.2 Functional Liver Preparation for Receptor Studies
1.3 Isolated Liver Cells
2 Hepatocyte Plasmalemma
2.1 Cell Surface Receptors
2.2 Lipid‐Receptor Interaction in Liver Plasmalemma
2.3 Surface‐to‐Cell and Cell‐to‐Cell Interactions in Hepatocytes
3 Liver Receptors Coupled to Cyclic Amp Stimulation
3.1 Adenylate Cyclase System
3.2 Identities and Specificities of Ns Protein
3.3 Specificities of Rs in Liver
4 Insulin and Growth Factor Receptors in Liver
4.1 General Characteristics
4.2 Receptors for Insulin
4.3 Receptors for Insulin‐Like Growth Factor I
4.4 Receptors for Insulin‐Like Growth Factor II
4.5 Receptors for Epidermal Growth Factor
4.6 Phosphokinasic Properties of Insulin and Polypeptide Growth Factor Receptors
5 Growth Hormone and Prolactin Receptors in Liver
6 Receptors to α1‐Agonists in Liver
6.1 General Characteristics
6.2 Receptors for Vasopressin
6.3 Receptors for Angiotensin II
6.4 Liver Receptors and Phosphoinositide‐Generated Second Messengers
7 Regulatory Role of Receptors for Gut Peptides in Liver
7.1 Degradation of Regulatory Peptides
7.2 Receptor‐Mediated Desensitization and Potentialization
7.3 General Characteristics of Receptor‐Mediated Processes Inside Hepatocytes
7.4 Disposal of Ligand and Binding Sites
7.5 Multiple Sites for Peptide Action in Hepatocytes
7.6 Multihormonal Regulation of Hepatocyte Function
8 Conclusion
Figure 1. Figure 1.

A: morphology of isolated hepatocytes. Left: phasecontrast microscopy; right: ultrastructural aspect. B: primary monolayer culture of hepatocytes within 4 h of plating. Ruthenium red intensely stains cell coat covering plasma membranes and penetrates narrow intercellular space between adjacent cells. × 7,000.

A from Rosselin et al. 313); B from Wanson et al. 377
Figure 2. Figure 2.

Schematic comparison of insulin (right) and epidermal growth factor (left) receptors. Hatched boxes, regions of high cysteine‐residue concentration; filled boxes, transmembrane domains; filled circles, single cysteine residues, possibly involved in formation of the α2β2 insulin receptor complex.

From Ullrich et al. 365). Reprinted by permission from Nature, copyright 1985, Macmillan Journals Limited
Figure 3. Figure 3.

A: relationship between ability of glucagon to stimulate cAMP production and corresponding fractional occupancy of glucagon receptor. Cyclic AMP levels and binding of glucagon were measured in the same experiment at 37°C in presence of 10 mM theophylline and different concentrations of glucagon (0‐2 × 10−8 M). In binding experiment, glucagon was supplemented with 10−10 M monoiodinated glucagon. B: relationship between relative activities of glucagon (•) and dehistidine glucagon (○) in inhibiting [14C]fructose flux into glycogen (expressed as percent of control) at selected peptide concentrations and corresponding fractional occupancies of high‐affinity hepatocyte glucagon receptor.

A from Rosselin 314); B from Bonnevie‐Nielsen and Tager 37
Figure 4. Figure 4.

Association of 125I‐labeled glucagon with solubilized glucagon receptors that bind (•) and do not bind (○) to wheat germ lectin as a function of glucagon concentration.—, Theoretical curves corresponding to dissociation constants for high‐affinity (left) and low‐affinity (right) binding as derived by mathematical modeling; each corresponds to a single binding equilibrium.

From Mason and Tager 244
Figure 5. Figure 5.

Specificity of vasoactive intestinal polypeptide (VIP) binding in liver. A: effect of unlabeled porcine VIP, synthetic secretin, peptide histidine isoleucine (PHI), and glucagon on the binding of 125I‐labeled VIP to rat liver membranes. Data are expressed as percent of initial binding of labeled VIP, that is, binding observed in absence of unlabeled peptide. Data are corrected for nonspecific binding, that is, binding observed in presence of an excess (10−6 M) of unlabeled porcine VIP. [Adapted from Bataille et al. 11,12.] B: inhibition of 125I‐VIP binding by increasing concentrations of unlabeled VIP, helodermin, secretin, and human pancreatic growth hormone‐releasing factor (hp GRF1–29‐NH2).

From Robberecht et al. 303
Figure 6. Figure 6.

Hepatic disappearance curves for somatostatin‐14 (S‐14), S‐28, and S‐25. The recognition of the R149 antibody resides in the COOH‐terminal part of somatostatin‐14 and somatostatin‐28, whereas that of R22 antibody is only present in the NH2‐terminal part of the somatostatin‐28. RIA, radioimmunoassay.

From Ruggere and Patel 318
Figure 7. Figure 7.

Homologous and heterologous desensitization. Left, kinetics of monolayer desensitization to glucagon. Cyclic AMP levels (filled triangles) after a first and second exposure to glucagon. Hepatocytes (15‐day‐old rat) were grown for 4 days with 10 μM cortisol. At day 4, 10 nM glucagon and 1 mM caffeine were added at time zero. Cultures were rapidly frozen at the time indicated on abscissa and analyzed for cAMP content by radioimmunoassay (A). Same experiment was repeated on cultures that had received a first dose of glucagon (10 nM) 4 h before (B). Control cultures that were grown in the absence of glucagon are represented by • and ○. Open symbols, cultures that have been incubated with 1 mM caffeine alone added at time zero. Middle, concentration dependence of homologous and heterologous desensitization to glucagon. Desensitization of cAMP accumulation in cultured hepatocytes as function of glucagon concentration during treatment. After treatment of cells for 12 h with 0.5 μM glucagon at the various concentrations indicated, cAMP accumulations stimulated by 0.5 μM glucagon (•) and 10 μM isoproterenol (○) were determined. Values are expressed as percentages of cAMP accumulation in untreated cells stimulated by glucagon and isoproterenol (550 and 438 pmol/mg of protein/5 min), respectively. Right, heterologous nature of desensitization by vasopressin. First, cells were desensitized by addition of increasing doses of vasopressin for 20 min. Residual phosphorylase A activities (○) were near basal level. Then control (0 concentration) or desensitized cells were stimulated for 90 s with maximally active doses of 1 nM vasopressin (•), 2 nM angiotensin (▵), 10 μM phenylephrine (□), or 5 nM glucagon (▵). Effect of vasopressin, angiotensin, and phenylephrine decreases with increasing doses of vasopressin.

Left from Plas and Nunez 284); middle from Noda et al. 269); right from Bréant et al. 41
Figure 8. Figure 8.

Nutritional relevance of the liver human growth hormone (hGH)‐binding sites. A: hGH binding in liver cells isolated from dwarf mice (•—•). After 30 days of 3,5,3‐triiodothyronine (T3) treatment, liver cells were isolated and binding of hGH was performed (•—•). Insert, treatment of hGH‐binding data according to the Scatchard method. B/F, ratio of bound to free hGH. The dw/dw mice exhibit a lack of both endogenous hGH and thyrotropic hormone. In those animals, lack of hGH‐binding sites could explain the low effect of hGH in promoting growth. Treatment with T3 increased the number of hGH‐binding sites and growth in hGH‐treated dw/dw mice. B: Correlation between plasma somatomedin‐C concentrations and liver bovine GH sites in control (•) and malnourished (○) rats. Linear correlation between plasma somatomedin‐C‐ and liver GH‐binding capacities is significant until day 28 (data shown between ordinate and —). Reduction of number of somatogenic‐binding sites in malnourished rats was associated with impaired production and/or release of somatomedin‐C in rats 14–28 days old.

A from Fouchereau‐Péron et al. 120); B from Maes et al. 234


Figure 1.

A: morphology of isolated hepatocytes. Left: phasecontrast microscopy; right: ultrastructural aspect. B: primary monolayer culture of hepatocytes within 4 h of plating. Ruthenium red intensely stains cell coat covering plasma membranes and penetrates narrow intercellular space between adjacent cells. × 7,000.

A from Rosselin et al. 313); B from Wanson et al. 377


Figure 2.

Schematic comparison of insulin (right) and epidermal growth factor (left) receptors. Hatched boxes, regions of high cysteine‐residue concentration; filled boxes, transmembrane domains; filled circles, single cysteine residues, possibly involved in formation of the α2β2 insulin receptor complex.

From Ullrich et al. 365). Reprinted by permission from Nature, copyright 1985, Macmillan Journals Limited


Figure 3.

A: relationship between ability of glucagon to stimulate cAMP production and corresponding fractional occupancy of glucagon receptor. Cyclic AMP levels and binding of glucagon were measured in the same experiment at 37°C in presence of 10 mM theophylline and different concentrations of glucagon (0‐2 × 10−8 M). In binding experiment, glucagon was supplemented with 10−10 M monoiodinated glucagon. B: relationship between relative activities of glucagon (•) and dehistidine glucagon (○) in inhibiting [14C]fructose flux into glycogen (expressed as percent of control) at selected peptide concentrations and corresponding fractional occupancies of high‐affinity hepatocyte glucagon receptor.

A from Rosselin 314); B from Bonnevie‐Nielsen and Tager 37


Figure 4.

Association of 125I‐labeled glucagon with solubilized glucagon receptors that bind (•) and do not bind (○) to wheat germ lectin as a function of glucagon concentration.—, Theoretical curves corresponding to dissociation constants for high‐affinity (left) and low‐affinity (right) binding as derived by mathematical modeling; each corresponds to a single binding equilibrium.

From Mason and Tager 244


Figure 5.

Specificity of vasoactive intestinal polypeptide (VIP) binding in liver. A: effect of unlabeled porcine VIP, synthetic secretin, peptide histidine isoleucine (PHI), and glucagon on the binding of 125I‐labeled VIP to rat liver membranes. Data are expressed as percent of initial binding of labeled VIP, that is, binding observed in absence of unlabeled peptide. Data are corrected for nonspecific binding, that is, binding observed in presence of an excess (10−6 M) of unlabeled porcine VIP. [Adapted from Bataille et al. 11,12.] B: inhibition of 125I‐VIP binding by increasing concentrations of unlabeled VIP, helodermin, secretin, and human pancreatic growth hormone‐releasing factor (hp GRF1–29‐NH2).

From Robberecht et al. 303


Figure 6.

Hepatic disappearance curves for somatostatin‐14 (S‐14), S‐28, and S‐25. The recognition of the R149 antibody resides in the COOH‐terminal part of somatostatin‐14 and somatostatin‐28, whereas that of R22 antibody is only present in the NH2‐terminal part of the somatostatin‐28. RIA, radioimmunoassay.

From Ruggere and Patel 318


Figure 7.

Homologous and heterologous desensitization. Left, kinetics of monolayer desensitization to glucagon. Cyclic AMP levels (filled triangles) after a first and second exposure to glucagon. Hepatocytes (15‐day‐old rat) were grown for 4 days with 10 μM cortisol. At day 4, 10 nM glucagon and 1 mM caffeine were added at time zero. Cultures were rapidly frozen at the time indicated on abscissa and analyzed for cAMP content by radioimmunoassay (A). Same experiment was repeated on cultures that had received a first dose of glucagon (10 nM) 4 h before (B). Control cultures that were grown in the absence of glucagon are represented by • and ○. Open symbols, cultures that have been incubated with 1 mM caffeine alone added at time zero. Middle, concentration dependence of homologous and heterologous desensitization to glucagon. Desensitization of cAMP accumulation in cultured hepatocytes as function of glucagon concentration during treatment. After treatment of cells for 12 h with 0.5 μM glucagon at the various concentrations indicated, cAMP accumulations stimulated by 0.5 μM glucagon (•) and 10 μM isoproterenol (○) were determined. Values are expressed as percentages of cAMP accumulation in untreated cells stimulated by glucagon and isoproterenol (550 and 438 pmol/mg of protein/5 min), respectively. Right, heterologous nature of desensitization by vasopressin. First, cells were desensitized by addition of increasing doses of vasopressin for 20 min. Residual phosphorylase A activities (○) were near basal level. Then control (0 concentration) or desensitized cells were stimulated for 90 s with maximally active doses of 1 nM vasopressin (•), 2 nM angiotensin (▵), 10 μM phenylephrine (□), or 5 nM glucagon (▵). Effect of vasopressin, angiotensin, and phenylephrine decreases with increasing doses of vasopressin.

Left from Plas and Nunez 284); middle from Noda et al. 269); right from Bréant et al. 41


Figure 8.

Nutritional relevance of the liver human growth hormone (hGH)‐binding sites. A: hGH binding in liver cells isolated from dwarf mice (•—•). After 30 days of 3,5,3‐triiodothyronine (T3) treatment, liver cells were isolated and binding of hGH was performed (•—•). Insert, treatment of hGH‐binding data according to the Scatchard method. B/F, ratio of bound to free hGH. The dw/dw mice exhibit a lack of both endogenous hGH and thyrotropic hormone. In those animals, lack of hGH‐binding sites could explain the low effect of hGH in promoting growth. Treatment with T3 increased the number of hGH‐binding sites and growth in hGH‐treated dw/dw mice. B: Correlation between plasma somatomedin‐C concentrations and liver bovine GH sites in control (•) and malnourished (○) rats. Linear correlation between plasma somatomedin‐C‐ and liver GH‐binding capacities is significant until day 28 (data shown between ordinate and —). Reduction of number of somatogenic‐binding sites in malnourished rats was associated with impaired production and/or release of somatomedin‐C in rats 14–28 days old.

A from Fouchereau‐Péron et al. 120); B from Maes et al. 234
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Article Title: Liver Receptors for Regulatory Peptides
 

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Gabriel Rosselin. Liver Receptors for Regulatory Peptides. Compr Physiol 2011, Supplement 17: Handbook of Physiology, The Gastrointestinal System, Neural and Endocrine Biology: 245-280. First published in print 1989. doi: 10.1002/cphy.cp060212