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- Title
Identification of a dysfunctional missense single nucleotide variant of human adenylyl cyclase VI.
- Authors
Gros, Robert; Qingming Ding; Henian Cao; Main, Tony; Hegele, Robert A.; Feldman, Ross D.
- Abstract
Genetic variants have been described for a range of G protein-coupled receptors (as well as for G proteins) linked to adenylyl cyclase. Furthermore, expression of these variants resulted in alterations in receptormediated activation of adenylyl cyclase, as well as alterations in more ‘downstream’ effector pathways mediated by cyclic adenosine monophosphate. However, the identification of dysfunctional variants of adenylyl cyclase has been far more limited. Screening a region of the molecule that we recently demonstrated to be critical in regulation of enzyme activity, we have identified a missense single-nucleotide variant at amino acid 674 of human adenylyl cyclase isoform VI. In a population of 286 healthy white subjects, this variant has an allelic frequency of 3.1% (although 0/90 nonwhite subjects had this variant). Expression of this variant of adenylyl cyclase VI (whether expressed as the S674 human adenylyl cyclase VI [ADCY6] or the S686 ADCY6 rat analog) is characterized by a significant decrease in stimulated adenylyl cyclase activity (forskolinstimulated activity of the S674 human ADCY6 variant was decreased to 56% ± 6% of the activity of the A674 variant [mean ± SEM]; n ± 9; P ± .004). Furthermore, subjects with the S674 variant demonstrated a significantly higher lymphocyte count (2.68 ± 4.13 × 103/mm3 versus 1.90 ± 0.72 × 103/mm3, P ± .019). Paralleling this phenotype, expression of the variant was associated with attenuation of the forskolinmediated reduction in cell growth rate to 64% ± 5% of the effect seen with expression of the wild-type ADCY6 (n = 4; P = .001). In summary, these data demonstrate an unappreciated variant of adenylyl cyclase isoform VI that has a functional impact on both enzyme activity and cyclic adenosine monophosphate-mediated regulation of cell growth. (Clin Pharmacol Ther 2005;77:271-8.)
- Subjects
ADENYLATE cyclase; ENZYME activation; ENZYME kinetics; ENZYME regulation; AMINO acids
- Publication
Clinical Pharmacology & Therapeutics, 2005, Vol 77, Issue 4, p271
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1016/j.clpt.2004.11.005