Increased enzyme activity and beta-adrenergic mediated vasodilation in subjects expressing a single-nucleotide variant of human adenylyl cyclase 6.
OBJECTIVE
cAMP is a critical regulator of metabolic and cardiovascular function. However, the role of genetic variability in the regulation of cAMP-mediated effects is unclear. Therefore, we assessed the effect of the expression of a recently identified missense genetic variant of adenylyl cyclase isoform 6 (ADCY6 S674).


RESULTS
In rat vascular smooth muscle cells, gene transfer of ADCY6 S674 increased adenylyl cyclase activity and arborization to a greater extent than gene transfer of ADCY6 A674. Similarly, in adherent mononuclear leukocyte cells isolated from ADCY6 S674-expressing human subjects, both adenylyl cyclase activity and adenylyl cyclase-mediated cell retraction were significantly increased. Additionally, in dorsal hand vein LVDT studies, subjects expressing the hyper-functional ADCY6 S674 variant had significantly greater vascular sensitivity to the beta-adrenergic agonist isoproterenol as assessed by both a greater potency and greater maximal effect than subjects expressing the ADCY6 A674 enzyme.


CONCLUSIONS
These data indicate that the expression of a novel, relatively common variant of ADCY6 parallels an increase in adenylyl cyclase activity and adenylyl cyclase-mediated function in humans.
Gros
Robert
R
Robarts Research Institute, P.O. Box 5015, 100 Perth Drive, London, Ontario, Canada.
Van Uum
Stan
S
Hutchinson-Jaffe
Adam
A
Ding
Qingming
Q
Pickering
J Geoffrey
JG
Hegele
Robert A
RA
Feldman
Ross D
RD
D000256:Adenoviridae / Q000235:genetics; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D048430:Cell Shape; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors; D005838:Genotype; D006225:Hand / Q000098:blood supply*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D014664:Vasodilation / Q000187:drug effects* / Q000235:genetics; D014680:Veins / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D007545:Isoproterenol