Chapter 171 – Adenylyl Cyclases

Publisher Summary This chapter presents the structure and catalytic mechanism of adenylyl cyclase (AC) and focuses on many modes of AC regulation. It also discusses normal and aberrant AC function in physiology and disease states. Hormonal and neurotransmitter regulation of AC occurs primarily through heterotrimeric G proteins in both vertebrates and invertebrates. Cell surface G protein-coupled receptor (GPCR) activation by extracellular stimuli in turn leads to activation of G proteins by initiating the exchange of GDP for GTP. The α subunit of the stimulatory G protein (Gsα) activates all nine tmACs in a nucleotide-dependent fashion. Gsα activation of ACs is terminated by GTP hydrolysis to GDP. The primary source of calcium ions is thought to be capacitative entry through Ca2+ channels. The only soluble mammalian AC isoform (sAC) is unique in its regulation and it is not affected by classic AC modulators such as G proteins, CaM, or forskolin. The sAC is activated by bicarbonate, and the bicarbonate ion induces a closure of the active site similar to the structural changes induced by Gsα on tmACs. The small molecule forskolin is a potent activator of all mammalian tmACs except AC9, which is weakly activated. While the binding site of forskolin is within the conserved catalytic domain, the stimulatory actions appear to be selective for membrane-bound vertebrate and invertebrate forms.