on October 4, 2007
Published online before print October 4, 2007, doi: 10.1161/ATVBAHA.107.145557
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Submitted on April 4, 2007
Accepted on September 12, 2007
Increased Enzyme Activity and Beta-Adrenergic–Mediated Vasodilation in Subjects Expressing a Single Nucleotide Variant of Human Adenylyl Cyclase 6
Robert Gros ;
From the Departments of Medicine and of Physiology & Pharmacology, University of Western Ontario, and Cell Biology and Vascular Biology Research Groups, Robarts Research Institute, London, Ontario, Canada.
* To whom correspondence should be addressed. E-mail: feldmanr{at}lhsc.on.ca.
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).
Methods and 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 
-adrenergic agonist isoproterenol as assessed by both a greater potency and greater maximal effect than subjects expressing the ADCY6 A674 enzyme.
Conclusion—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.
Key words: smooth muscle • adenylyl cyclase • vasodilation