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Functional Selectivity of G Protein-Coupled Receptor Ligands pp 107–124Cite as

Functional Selectivity at Adrenergic Receptors

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Part of the book series: The Receptors ((REC))

Abstract

The adrenergic receptors have been a model for understanding the structure, function, regulation, and biology of GPCRs. They play a similar role with respect to ligand functional selectivity (or ligand-dependent differential signaling). The β-adrenergic receptor has provided key structural information about ligand binding and also rich biophysical data demonstrating that different ligands can produce different conformational states of the receptor. There is also substantial data in cell systems showing that ligands can produce distinct spectrums of response including differential roles of the Gi and Gs-type G proteins as well as contrasting agonist and inverse agonist actions at G protein-dependent and G protein-independent (largely β-arrestin-dependent) signals. There is also in vivo evidence for physiologically important roles for these different signals. The clinical importance of β-adrenergic blockers in cardiovascular disease and emerging evidence for ligand-specific vs. class-specific effects in clinical studies makes a full understanding of ligand functional selectivity very important. Challenges in the future will be to determine the unique receptor conformations produced by the binding of different ligands, show how those conformations interact with the complex cellular context and regulatory processes to result in unique signal output patterns, and finally to translate that basic knowledge into novel therapeutics that take advantage of the additional specificity provided by ligand functional selectivity.

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Abbreviations

AC:

Adenylyl cyclase

βArr:

Beta arrestin

cAMP:

3′5′ cyclic adenosine monophopshpate

CHO:

Chinese hamster ovary cell line

ERK:

Extracellular signal regulated kinase

Gi:

Inhibitory guanine nucleotide binding protein

GPCR:

G protein coupled receptor

Gs:

Stimulatory guanine nucleotide binding protein

HEK:

Human embryonic kidney cell line

MAP kinase:

Mitogen activated protein kinases

mBB:

Monobromobimane

PDZ:

Pleckstrin, discs large, Zo-1 homology domain

PI3K:

Phosphatidyl inositol 3-kinase

PKA:

cAMP dependent protein kinase (protein kinase A)

RET:

Resonance energy transfer

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Acknowledgments

Work in the author’s lab described here was supported by NIH R01GM39561.

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  1. Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI, 48109

    Richard R. Neubig

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Correspondence to Richard R. Neubig .

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  1. VA Medical Center, 3710 SW US Veterans Hospital Road, 97239-2999, Portland, OR, USA

    Kim A. Neve

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Neubig, R.R. (2009). Functional Selectivity at Adrenergic Receptors. In: Neve, K.A. (eds) Functional Selectivity of G Protein-Coupled Receptor Ligands. The Receptors. Humana Press. https://doi.org/10.1007/978-1-60327-335-0_7

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