title: Novel human alpha1a-adrenoceptor single nucleotide polymorphisms alter receptor pharmacology and biological function.
abstract: We identified nine naturally-occurring human single nucleotide polymorphisms (SNPs) in the alpha(1a)-adrenoceptor (alpha(1a)AR) coding region, seven of which result in amino acid change. Utilizing rat-1 fibroblasts stably expressing wild type alpha(1a)AR or each SNP at both high and low levels, we investigated the effect of these SNPs on receptor function. Compared with wild type, two SNPs (R166K, V311I) cause a decrease in binding affinity for agonists norepinephrine, epinephrine, and phenylephrine, and also shift the dose-response curve for norepinephrine stimulation of inositol phosphate (IP) production to the right (reduced potency) without altering maximal IP activity. In addition, SNP V311I and I200S display altered antagonist binding. Interestingly, a receptor with SNP G247R (located in the third intracellular loop) displays increased maximal receptor IP activity and stimulates cell growth. The increased receptor signaling for alpha(1a)AR G247R is not mediated by altered ligand binding or a deficiency in agonist-mediated desensitization, but appears to be related to enhanced receptor-G protein coupling. In conclusion, four naturally-occurring human alpha(1a)AR SNPs induce altered receptor pharmacology and/or biological activity. This finding has potentially important implications in many areas of medicine and can be used to guide alpha(1a)AR SNP choice for future clinical studies.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Beilei
authors.initials: B
authors.lastname: Lei
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Morris
authors.forename: Michael P
authors.initials: MP
authors.lastname: Smith
authors.forename: Laura P
authors.initials: LP
authors.lastname: Svetkey
authors.forename: Mark F
authors.initials: MF
authors.lastname: Newman
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchanan
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Beckstrom-Sternberg
authors.forename: Eric D
authors.initials: ED
authors.lastname: Green
authors.forename: Debra A
authors.initials: DA
authors.lastname: Schwinn
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018340:Receptors, Adrenergic, alpha-1; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D019204:GTP-Binding Proteins