Novel human α1a-adrenoceptor single nucleotide polymorphisms alter receptor pharmacology and biological function

Beilei Lei, Daniel P. Morris, Michael P. Smith, Laura P. Svetkey, Mark F. Newman, Jerome I. Rotter, Thomas A. Buchanan, Stephen M. Beckstrom-Sternberg, Eric D. Green, Debra A. Schwinn

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)229-239
Number of pages11
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume371
Issue number3
DOIs
StatePublished - Mar 2005

Bibliographical note

Funding Information:
Acknowledgements This study was supported in part by NIH grants #AG17556 (DAS), #HL67974 (JIR), #HL55005 (TAB), NCRR#RR43 (TAB), NCRR#RR30 (DAS) and a NHGRI Visiting Investigator Program (VIP) Award (DAS), NHGRI (EDG), and the Cedar-Sinai, Board of Governors’ Chair in Medical Genetics (JIR). Dr. Schwinn is a senior fellow in the Center for the Study of Aging and Human Development at Duke University. We would like to take this opportunity to thank Jackie Idol for technical assistance in defining human α1aAR polymorphisms, Gregory A. Michelotti, PhD, for helpful conversations, and Zarrin T. Brooks for assistance in manuscript preparation.

Funding

Acknowledgements This study was supported in part by NIH grants #AG17556 (DAS), #HL67974 (JIR), #HL55005 (TAB), NCRR#RR43 (TAB), NCRR#RR30 (DAS) and a NHGRI Visiting Investigator Program (VIP) Award (DAS), NHGRI (EDG), and the Cedar-Sinai, Board of Governors’ Chair in Medical Genetics (JIR). Dr. Schwinn is a senior fellow in the Center for the Study of Aging and Human Development at Duke University. We would like to take this opportunity to thank Jackie Idol for technical assistance in defining human α1aAR polymorphisms, Gregory A. Michelotti, PhD, for helpful conversations, and Zarrin T. Brooks for assistance in manuscript preparation.

FundersFunder number
National Institutes of Health (NIH)55005, 67974, 17556
National Institutes of Health (NIH)
National Human Genome Research InstituteZ01HG000060
National Human Genome Research Institute
National Center for Research Resources

    Keywords

    • Human
    • Inositol phosphate
    • Polymorphism
    • Receptor/G protein coupling
    • Signal transduction
    • Single nucleotide polymorphisms
    • α-Adrenoceptor

    ASJC Scopus subject areas

    • Pharmacology

    Fingerprint

    Dive into the research topics of 'Novel human α1a-adrenoceptor single nucleotide polymorphisms alter receptor pharmacology and biological function'. Together they form a unique fingerprint.

    Cite this