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(2)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 Del322-325) 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 Del322-325 variant had decreased high affinity agonist binding (K(H) = 7.3 +/- 0.95 versus 3.7 +/- 0.43 nm; %R(H) = 31 +/-4 versus 49 +/-4) compared with wild-type indicating impaired formation of the agonist-receptor-G 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 ( approximately 71% impaired) and inositol phosphate production ( approximately 60% impaired) was also found with the polymorphic receptor. The Del322-325 receptor was approximately 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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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(2)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 Del322-325) 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 Del322-325 variant had decreased high affinity agonist binding (K(H) = 7.3 +/- 0.95 versus 3.7 +/- 0.43 nm; %R(H) = 31 +/-4 versus 49 +/-4) compared with wild-type indicating impaired formation of the agonist-receptor-G 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 ( approximately 71% impaired) and inositol phosphate production ( approximately 60% impaired) was also found with the polymorphic receptor. The Del322-325 receptor was approximately 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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J. Biol. Chem.
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| uniprot:author |
Bridges K.M.,
Forbes S.L.,
Liggett S.B.,
Rahman F.F.,
Small K.M.
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| uniprot:date |
2000
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| uniprot:pages |
23059-23064
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| uniprot:title |
A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors.
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| uniprot:volume |
275
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| dc-term:identifier |
doi:10.1074/jbc.M000796200
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