Abstract
Nicotinic acetylcholine receptors (nAChRs) are combinations of subunits arranged as pentamers encircling a central cation channel. At least nine α and four β subunits are expressed in the central and peripheral nervous systems; their presence in autonomic ganglia, the adrenal medulla, and central nervous system, with accompanying responses elicited by nicotinic agonists, point to their involvement in cardiovascular homeostasis. nAChRs formed by α3, α5, and β4 subunits may regulate blood pressure (BP) by mediating release of catestatin, the endogenous nicotinic antagonist fragment of chromogranin A (CHGA) and potent inhibitor of catecholamine secretion. Genes encoding these subunits (CHRNA3, CHRNA5, and CHRNB4) are clustered on human chromosome 15q24. Because variation in this cluster may alter autonomic regulation of BP, we sequenced ∼15 kilobase pairs in 15q24 containing their coding and 5′- and 3′-untranslated regions in 80 individuals. We identified 63 variants: 25 in coding regions of CHRNA3, CHRNA5, and CHRNB4 and 48 noncoding single-nucleotide polymorphisms (SNPs). Haplotype frequencies varied across ethnic populations. We assessed the contribution of six SNPs in the putative catestatin binding region of CHRNA3 and CHRNB4 to autonomic traits. In twins, catestatin and BP were heritable. CHRNA3 SNPs and haplotypes containing K95K (G285A) associated with circulating plasma catestatin, epinephrine levels, as well as systolic BP, suggesting altered coupling of the nAChRs to BP. Studies of chromaffin cells in vitro reveal that nicotinic agonist stimulation releases catecholamines and CHGA, a process augmented by overexpression of CHRNA3 and blocked by catestatin. These cellular events suggest a homeostatic mechanism underlying the pleiotropic actions of CHRNA3 genetic variation on autonomic function observed in twins.
- nAChR, nicotinic acetylcholine receptor
- CHGA, chromogranin A
- CNS, central nervous system
- ACh, acetylcholine
- BP, blood pressure
- SNP, single-nucleotide polymorphism
- bp, base pair(s)
- EAP, embryonic alkaline phosphatase
- h2, heritability
- UTR, untranslated region
- kb, kilobase(s)
- LD, linkage disequilibrium
- SBP, systolic blood pressure
- BW284c51, 1,5-bis (4-allyldimethylammoniumphenyl)-pentan-3-one dibromide.
Footnotes
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This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant P01-HL58120]; the National Institutes of Health Pharmacogenetics Research Network [Grant U01-HL69758]; the National Institutes of Health National Institute of General Medical Sciences [Grant R37-GM18360]; the National Institutes of Health National Institute Diabetes and Digestive and Kidney Diseases [Grant R01-DK60702]; the National Institutes of Health National Center on Minority Health and Health Disparities [Grant MD000220]; the National Institutes of Health National Institute on Drug Abuse [Grant DA019372]; and the National Institutes of Health National Center for Research Resources [Grant RR00827] (University of California, San Diego General Clinical Research Center).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.157271
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
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B.K.R. and J.W. contributed equally to this work.
- Received June 5, 2009.
- Accepted August 6, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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