UC San Diego

The widely conserved cyclic adenosine monophosphate (cAMP) signaling pathway governs multiple physiological responses. Mammals express two types of adenylyl cyclases : transmembrane adenylyl cyclase (tmAC), and soluble adenylyl cyclase (sAC). The distinct regulatory properties, tissue specificity and cellular distributions of the adenylyl cyclases make them attractive targets for research and drug development. While P-site inhibitors preferentially inhibit tmAC isoforms, drugs derived from catechol estrogens (4CE) and KH7 selectively inhibit sAC. All of the existing adenylyl cyclase stimulators are analogs of the tmAC activator forskolin. There are currently no pharmacological stimulators of sAC in literature. In this study, I took advantage of the high rate of cAMP production in coral tissue homogenates to screen the effects of 151 pure compounds derived from natural products. 50 [mu]M Laurencione monoacetate stimulated cAMP production in coral tissues by 60%, with an EC₅₀ of ~25 nM--1 [mu]M. The same treatment also stimulated purified rat sACt activity by 80%, with an EC₅₀ lower than 5 nM. This effect on rat sACt was not evident with 25 mM HCO₃⁻. Though cAMP accumulation assays in live cells suggested cross-talk effects with laurencione monoacetate, a Western blot detecting proteins phosphorylated by PKA suggested that the compound affected intracellular PKA activity. This study demonstrates that corals are useful subjects for screening compounds that affect cAMP production, and that natural products are good candidates for drug discovery. Identification of a sAC- specific stimulator that can be used as a pharmacological tool is challenging due to the complexity of the cAMP signaling pathway