Nine membrane-bound adenylyl cyclase isoforms catalyze the production of the second messenger cyclic AMPs (cAMP) in response to various stimuli. Reduction of adenylyl cyclase activity has well-documented benefits, including for heart disease and pain. These roles have inspired an attempt to develop isoform selective adenylyl cyclase inhibitors. The lack of true selectivity currently limits exploration of functions and/or treatment of dysfunctions involving adenylyl cyclase/cAMP signaling. The present study demonstrated that a panel of inhibitors described as AC5-selective actually does not discriminate between AC5 and AC6. Likewise, the putative AC1-selective inhibitor, NB001 [5-[[2-(6-amino-9H-purin-9-yl)ethyl]amino]-1-pentanol], does not directly target AC1 to reduce cAMP levels. These results lead to a discussion regarding the need to reinterpret literature using AC5/6-selective molecules.
See article at J Pharmacol Exp Ther 2013, 347:265–275.
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