We identified nine naturally-occurring human single nucleotide polymorphisms (SNPs) in the α1a-adrenoceptor (α1aAR) coding region, seven of which result in amino acid change. Utilizing rat-1 fibroblasts stably expressing wild type α1aAR 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 α1aAR 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 α1aAR 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 α1aAR SNP choice for future clinical studies.
- Inositol phosphate
- Receptor/G protein coupling
- Signal transduction
- Single nucleotide polymorphisms
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