Pharmacological modulation of the CO2/HCO3−/pH-, calcium-, and ATP-sensing soluble adenylyl cyclase

Cyclic AMP (cAMP), the prototypical second messenger, has been implicated in a wide variety of (often opposing) physiological processes. It simultaneously mediates multiple, diverse processes, often within a single cell, by acting locally within independently-regulated and spatially-restricted microdomains. Within each microdomain, the level of cAMP will be dependent upon the balance between its synthesis by adenylyl cyclases and its degradation by phosphodiesterases (PDEs). In mammalian cells, there are many PDE isoforms and two types of adenylyl cyclases; the G protein regulated transmembrane adenylyl cyclases (tmACs) and the CO2/HCO3−/pH-, calcium-, and ATP-sensing soluble adenylyl cyclase (sAC). Discriminating the roles of individual cyclic nucleotide microdomains requires pharmacological modulators selective for the various PDEs and/or adenylyl cyclases. Such tools present an opportunity to develop therapeutics specifically targeted to individual cAMP dependent pathways. The pharmacological modulators of tmACs have recently been reviewed, and in this review, we describe the current status of pharmacological tools available for studying sAC.