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Article

Multiple Signaling States of G-Protein-Coupled Receptors

Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio

Abstract

I. Introduction

A. Basic Receptor/G-Protein-Coupling Principles

II. Receptor Theories

A. Ternary Complex and Modified/Revised Ternary Complex

B. Alternative Models

III. Agonist-Specific Signaling States

A. Evidence from Multiple G-Protein Coupling or Efficacy

B. Evidence from Kinetic/Binding Studies

1. Ligands.

2. GTP Analogs.

3. Fluorescent and Biophysical Studies.

C. Evidence from Reversal of Efficacy (i.e., Protean Agonism)

1. Native Systems.

2. Transfected Systems.

D. Evidence from Differential Phosphorylation, Desensitization, Internalization, and Palmitoylation

E. Evidence from Inverse Agonism

F. Evidence from Fusion Chimeras

IV. Lessons from Rhodopsin

A. Structural Basis for Mechanism of Activation in a G-Protein-Coupled Receptor, Mammalian Rhodopsin

B. Lessons from Activation-Induced Events in the Rhodopsin Molecule

C. Steric Changes in Chromophore

D. Electrostatic Changes in Opsin

E. Specific Transmembrane Helical Movements in Opsin

F. Theory for Activation-Induced Conformations

G. Lessons from Gain of Function Rhodopsin Mutations

H. Lessons from the Mechanism of Loss of Function Caused in Retinitis Pigmentosa Mutations

I. Rhodopsin as the Primer

V. Therapeutic Implications

A. G-Protein-Coupled Receptor Diseases Caused by Unregulated Internalization

B. Differential Use of {beta}-Adrenergic Receptor Blockers

C. Morphine Dependence and Tolerance

D. Use of Stimulation-Biased Assay Systems

Studies have been amassed in the past several years indicating that an agonist can conform a receptor into an activation state that is dependent upon an intrinsic property of the agonist usually based upon its chemical composition. Theoretically, each different agonist could impart its own unique activation state. Evidence for multiple signaling states for the G-protein-coupled receptors will be reviewed and is derived from many different pharmacological behaviors: efficacy, kinetics, protean agonism, differential desensitization and internalization, inverse agonism, and fusion chimeras. A recent extension of the ternary complex model is suggested by evidence that the different processes that govern deactivation, such as desensitization and internalization, is also regulated by conformers specific to the agonist. Rhodopsin may serve as a primer for the study of multiple activation states. Therapeutic implications that utilize multiple signaling states hold vast promise in the rationale design of drugs.

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