Comprehensive Physiology Wiley Online Library

Regulation of G Protein–Coupled Receptors

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Signaling Via G Protein–Coupled Receptor Pathways
1.1 G Protein–Coupled Receptors
1.2 G Proteins
1.3 Effectors
2 Mechanisms of G Protein–Coupled Receptor Regulation
2.1 Classification of Desensitization
2.2 The Beta‐Adrenergic Receptor and Rhodopsin Signaling Pathways: Model Systems of GPR Signaling and Regulation
2.3 Receptor Phosphorylation And Uncoupling: Rapid Desensitization
2.4 Receptor Sequestration
2.5 Receptor Down‐Regulation
2.6 Receptor Polymorphisms
2.7 Sensitization
2.8 Desensitization of Other GPR Pathways
3 Summary
Figure 1. Figure 1.

Proposed topology of the human β2‐adrenergic receptor (β2AR). The amino acid sequence of the human β2AR, as it is proposed to reside in the plasma membrane, is shown. The amino acids identical in the human β1‐, β2‐, β3‐, and turkey β1‐adrenergic receptors are shaded. [From Gomez and Benovic , with permission from Academic Press.]

Figure 2. Figure 2.

G protein–coupled receptor activation of effector. See text for description. [From Clapham and Neer , with permission from Nature.]

Figure 3. Figure 3.

Models of rapid desensitization of β2AR‐mediated cAMP production. A. Homologous desensitization. Cells are pretreated with a high concentration of beta‐agonist (10 μM isoproterenol) for 30 min, washed extensively with cold phosphate‐buffered saline, then re‐challenged with isoproterenol in a concentration‐dependent manner for 10 min. Reactions are stopped and cAMP is isolated and quantitated by radioimmunoassay. Concentration‐dependent response to isoproterenol stimulation exhibits a significant reduction in maximal cAMP accumulation (reduced Bmax) and a reduction in sensitivity to isoproterenol (increased EC50). B. Heterologous desensitization. Experiment identical to that described in A, except cells are pretreated for 30 min with a cAMP‐generating agent (forskolin or PGE1) other than beta‐agonist. Concentration‐dependent response to isoproterenol stimulation exhibits a significant increase in EC50 with little or no loss in Bmax.

Figure 4. Figure 4.

Comparison of the amino acid sequence of related GRKs by dendogram analysis. The PILEUP program in the Wisconsin Genetics Computer Group (GCG) software was used to align and compare amino acid sequences of bovine GRK1 (rhodopsin kinase), GRK2 (βARK1), GRK3 (βARK2), human GRK4 (IT11), GRK5, GRK6, and Drosophila GPRK‐1 and GPRK‐2. See Benovic and Gomez for detailed sequence comparisons. PILEUP uses a progressive pairwise alignment as previously described .

Figure 5. Figure 5.

Stimulus‐dependent phosphorylation and desensitization of rhodopsin and the β2AR. Receptor activation, either by light (rhodopsin) or a β‐agonist (β2AR), promotes interaction of the receptor with transducin or Gs, respectively, leading to G protein and effector activation. Receptor activation also promotes phosphorylation of the receptor, which is mediated either by rhodopsin kinase or βARK. Phosphorylation of the receptor appears to uncouple it partially from the G protein, but also promotes its interaction with arrestin (for rhodopsin) or β‐arrestin (for β2AR). This interaction further uncouples the receptor from the G protein. Desphosphorylation of rhodopsin requires regeneration with 11 −cis retinal, which is followed by arrestin dissociation and dephosphorylation of the receptor by phosphatase 2A. The mechanism of β2AR dephosphorylation remains poorly understood but may involve sequestration of the receptor into a compartment where dephosphorylation can occur. [From Palczewski and Benovic , with permission from Trends in Biochemical Sciences.]



Figure 1.

Proposed topology of the human β2‐adrenergic receptor (β2AR). The amino acid sequence of the human β2AR, as it is proposed to reside in the plasma membrane, is shown. The amino acids identical in the human β1‐, β2‐, β3‐, and turkey β1‐adrenergic receptors are shaded. [From Gomez and Benovic , with permission from Academic Press.]



Figure 2.

G protein–coupled receptor activation of effector. See text for description. [From Clapham and Neer , with permission from Nature.]



Figure 3.

Models of rapid desensitization of β2AR‐mediated cAMP production. A. Homologous desensitization. Cells are pretreated with a high concentration of beta‐agonist (10 μM isoproterenol) for 30 min, washed extensively with cold phosphate‐buffered saline, then re‐challenged with isoproterenol in a concentration‐dependent manner for 10 min. Reactions are stopped and cAMP is isolated and quantitated by radioimmunoassay. Concentration‐dependent response to isoproterenol stimulation exhibits a significant reduction in maximal cAMP accumulation (reduced Bmax) and a reduction in sensitivity to isoproterenol (increased EC50). B. Heterologous desensitization. Experiment identical to that described in A, except cells are pretreated for 30 min with a cAMP‐generating agent (forskolin or PGE1) other than beta‐agonist. Concentration‐dependent response to isoproterenol stimulation exhibits a significant increase in EC50 with little or no loss in Bmax.



Figure 4.

Comparison of the amino acid sequence of related GRKs by dendogram analysis. The PILEUP program in the Wisconsin Genetics Computer Group (GCG) software was used to align and compare amino acid sequences of bovine GRK1 (rhodopsin kinase), GRK2 (βARK1), GRK3 (βARK2), human GRK4 (IT11), GRK5, GRK6, and Drosophila GPRK‐1 and GPRK‐2. See Benovic and Gomez for detailed sequence comparisons. PILEUP uses a progressive pairwise alignment as previously described .



Figure 5.

Stimulus‐dependent phosphorylation and desensitization of rhodopsin and the β2AR. Receptor activation, either by light (rhodopsin) or a β‐agonist (β2AR), promotes interaction of the receptor with transducin or Gs, respectively, leading to G protein and effector activation. Receptor activation also promotes phosphorylation of the receptor, which is mediated either by rhodopsin kinase or βARK. Phosphorylation of the receptor appears to uncouple it partially from the G protein, but also promotes its interaction with arrestin (for rhodopsin) or β‐arrestin (for β2AR). This interaction further uncouples the receptor from the G protein. Desphosphorylation of rhodopsin requires regeneration with 11 −cis retinal, which is followed by arrestin dissociation and dephosphorylation of the receptor by phosphatase 2A. The mechanism of β2AR dephosphorylation remains poorly understood but may involve sequestration of the receptor into a compartment where dephosphorylation can occur. [From Palczewski and Benovic , with permission from Trends in Biochemical Sciences.]

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Raymond B. Penn, Jeffrey L. Benovic. Regulation of G Protein–Coupled Receptors. Compr Physiol 2011, Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology: 125-164. First published in print 1998. doi: 10.1002/cphy.cp070107