Key result
The putative AC5-selective inhibitors SQ22,536, NKY80, and vidarabine inhibited cardiac adenylyl cyclase from wild type and AC5 knockout mice with similar potencies, demonstrating a lack of adequate selectivity for AC5.
Putative AC5-selective inhibitors lack adequate selectivity and AC regulation in AC5KO hearts is unimpaired, questioning the dominant role of AC5 in the heart and the utility of these inhibitors for studying AC5-specific functions.
These inhibitors should not be used as AC5-selective tools; leaves open AC5's dominant role in cardiac regulation.
Adenylyl cyclase type 5 (AC5) was described as major cardiac AC isoform. The knockout of AC5 (AC5KO) exerted cardioprotective effects in heart failure. Our study explored the impact of AC5KO on mouse heart AC activities and evaluated putative AC5-selective inhibitors. In cardiac membranes from AC5KO mice, basal AC activity was decreased, while AC stimulation was intact. The putative AC5-selective P-site inhibitors SQ22,536 [9-(tetra-hydro-2-furanyl)-9H-purin-6-amine], vidarabine (9-β-D-arabinosyladenine) and NKY80 [2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone] inhibited recombinant AC5 more potently than AC2 and AC1, but selectivity was only modest (∼4-40-fold). These compounds inhibited cardiac AC from WT and AC5KO mice with similar potencies. In conclusion, AC regulation in AC5KO hearts was unimpaired, questioning the supposed dominant role of AC5 in the heart. Moreover, the AC inhibitors SQ22,536, NKY80 and vidarabine lack adequate selectivity for AC5 and, therefore, do not present suitable tools to study AC5-specific functions.
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Braeunig et al. (2013) studied Heart Failure (Preclinical Model). Putative AC5-selective P-site inhibitors (SQ22,536, vidarabine, NKY80) vs. Wild type vs AC5 knockout mice was evaluated on Inhibition of cardiac adenylyl cyclase (AC) activity (IC50). The putative AC5-selective inhibitors SQ22,536, NKY80, and vidarabine inhibited cardiac adenylyl cyclase from wild type and AC5 knockout mice with similar potencies, demonstrating a lack of adequate selectivity for AC5.
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