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Article

Autonomic Nervous System Pharmacogenomics: A Progress Report

Departments of Pharmacology and Medicine, University of California, San Diego, La Jolla, California

Abstract

I. Introduction

II. Cholinergic Receptors

A. Nicotinic Cholinergic Receptors

B. Muscarinic Cholinergic Receptors

III. Adrenergic Receptors

A. {alpha}1-Adrenergic Receptors

1. {alpha}1A-Adrenergic Receptors.

2. {alpha}1B-Adrenergic Receptors.

B. {alpha}2-Adrenergic Receptors

1. {alpha}2A-Adrenergic Receptors.

2. {alpha}2B-Adrenergic Receptors.

3. {alpha}2C-Adrenergic Receptors.

C. {beta}-Adrenergic Receptors

1. {beta}1-Adrenergic Receptors.

2. {beta}2-Adrenergic Receptors.

a. {beta}2-Adrenergic Receptor Polymorphisms and Haplotypes.

b. 5' Noncoding {beta}2-Adrenergic Receptor Polymorphisms and Receptor Expression.

c. {beta}2-Adrenergic Receptor Polymorphisms, Desensitization, and Down-Regulation.

d. {beta}2-Adrenergic Receptor Polymorphisms and Hypertension.

e. {beta}2-Adrenergic Receptor Polymorphisms and Vascular Responses to Agonists.

f. {beta}2-Adrenergic Receptor Polymorphisms and Congestive Heart Failure.

g. {beta}2-Adrenergic Receptor Polymorphisms and Obesity.

h. {beta}2-Adrenergic Receptor Polymorphisms and Asthma.

3. {beta}3-Adrenergic Receptors.

IV. Summary and Conclusions

V. Outlook

Pharmacogenetics, the inherited basis for interindividual differences in drug response, has rapidly expanded with the advent of new molecular tools and the sequencing of the human genome, yielding pharmacogenomics. We review here recent ideas and findings regarding pharmacogenomics of components of the autonomic nervous system, in particular, neuronal nicotinic acetylcholine receptors, postsynaptic receptors with which the parasympathetic and sympathetic neurotransmitters, acetylcholine (ACh) and norepinephrine, respectively, interact. The receptor subtypes that mediate these responses, M_1-3 muscarinic cholinergic receptors (mAChRs), and _1A,B,D-, _2A,B,C-, and _1,2,3-adrenergic receptors (AR), show highly variable expression of genetic variants; variants of mAChRs and ₁-ARs are relatively rare, whereas ₂-AR and -AR subtype variants are quite common. The largest amount of data is available regarding variants of the latter ARs and represents efforts to associate certain receptor genotypes, most commonly, single nucleotide polymorphisms, with particular phenotypes (e.g., cardiovascular and metabolic responses). In vitro and in vivo studies have yielded inconsistent results; definitive conclusions are limited. We identify several conceptual and methodological problems with available data: sample size, ethnicity, tissue differences, coding versus noncoding variants, limited studies of haplotypes, and interaction among variants. Thus, although progress has been made in identifying genetic variation that influences drug response for autonomic nervous system components, we are still at the early stages of defining the most critical genetic determinants and their role in human physiology and pharmacology.

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