Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 275, Issue 30, Pages 23059-23064Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M000796200
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- NHLBI NIH HHS [HL53436, HL41496] Funding Source: Medline
- NIEHS NIH HHS [ES06096] Funding Source: Medline
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The alpha(2)-adrenergic receptors (alpha(2)ARs) play a critical role in modulating neurotransmitter release in the central and peripheral sympathetic nervous systems. A polymorphism of the alpha(2C)AR subtype localized to human chromosome 4 (the pharmacologic alpha(2C)AR subtype) within an intracellular domain has been identified in normal individuals. The polymorphism (denoted De1322-325) is because of an in-frame 12-nucleic acid deletion encoding a receptor lacking Gly-Ala-Gly-Pro in the third intracellular loop. To delineate the functional consequences of this structural alteration, Chinese hamster ovary cells were permanently transfected with constructs encoding wild-type human alpha(2C)AR and the polymorphic receptor, The De1322-325 variant had decreased high affinity,agonist binding (K-H = 7.3 +/- 0.95 vel sus 3.7 +/- 0.43 nM; %R-H = 31 +/- 4 versus 49 +/- 4) compared with wild-type indicating impaired formation of the agonist-receptor-C: protein complex, The polymorphic receptor displayed markedly depressed epinephrine-promoted coupling to G(i), inhibiting adenylyl cyclase by 10 +/- 4.3% compared with 73 +/- 2.4% for wild-type alpha(2C)AR, This also was so for the endogenous ligand norepinephrine and full and partial synthetic agonists, Depressed agonist-promoted coupling to the stimulation of MAP kinase (similar to 71% impaired) and inositol phosphate production (similar to 60% impaired) was also found with the polymorphic receptor. The Del322-325 receptor was similar to 10 times more frequent in African-Americans compared with Caucasians (allele frequencies 0.381 versus 0.040). Given this significant loss of function phenotype in several signal transduction cascades and the skewed ethnic prevalence, Del322-325 represents a pharmacoethnogenetic locus and may also be the basis for interindividual variation in cardiovascular or central nervous system pathophysiology.
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