Natural variation within the neuronal nicotinic acetylcholine receptor cluster on human chromosome 15q24: influence on heritable autonomic traits in twin pairs.
Nicotinic acetylcholine receptors (nAChRs) are combinations of subunits arranged as pentamers encircling a central cation channel. At least nine alpha and four beta 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 alpha3, alpha5, and beta4 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 approximately 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.
Rana
Brinda K
BK
Departments of Psychiatry, University of California at San Diego, La Jolla, California 92093-0657, USA.
Wessel
Jennifer
J
Mahboubi
Vafa
V
Rao
Fangwen
F
Haeller
Jeannine
J
Gayen
Jiaur R
JR
Eskin
Eleazar
E
Valle
Anne M
AM
Das
Madhusudan
M
Mahata
Sushil K
SK
Taupenot
Laurent
L
Stridsberg
Mats
M
Talley
Todd T
TT
Ziegler
Michael G
MG
Smith
Douglas W
DW
Schork
Nicholas J
NJ
O'Connor
Daniel T
DT
Taylor
Palmer
P
D000110:Acetylcholinesterase / Q000097:blood; D000483:Alleles; D001341:Autonomic Nervous System / Q000502:physiology*; D002395:Catecholamines / Q000097:blood; D053379:Chromogranin A / Q000235:genetics; D002864:Chromogranins / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005006:Ethnicity; D005089:Exocytosis / Q000187:drug effects; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008958:Models, Molecular; D005810:Multigene Family; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014481:United States / Q000453:epidemiology
D002395:Catecholamines; D053379:Chromogranin A; D002864:Chromogranins; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C109084:chromogranin A (344-364); D000110:Acetylcholinesterase