[Adenylyl cyclase--isoforms, regulation and function]

Abstract

Since its discovery in 1956, cyclic AMP (cAMP) has been shown to be a ubiquitous second messenger. It functions as one of many signaling molecules enabling cells to respond to external signals. cAMP is synthesized by adenylyl cyclases (ACs), enzymes that convert adenosine triphosphate (ATP) to cAMP. Three classes of ACs have been cloned based on the conservation of their catalytic domains; they include: class I-ACs from Enterobacteria, including Escherichia coli; class II-"toxic" ACs, including calmodulin-activated enzymes from Bordetella pertussis and Bacillus anthracis; class III-ACs homologues from bacteria to human; they include nine isoformes found in mammals, and designated AC-1 to AC-9. Although ACs can exist in particulate and soluble forms, the former form predominates-at least in mammals. Nine (AC-1-AC-9) mammalian enzymes are stimulated by an "alpha" subunit of Gs-protein (Gs alpha) and by the diterpene forskolin, albeit to varying degrees (with AC-9 being least sensitive to forskolin). In addition to their core signaling capability in response to signals from Gs alpha, the different ACs are capable of receiving signals from a variety of sources, including other G-protein subunits, such as Gi alpha (inhibitory) or G beta gamma (stimulatory or inhibitory, depending on the enzyme), protein kinases (protein kinase A, PKA; protein kinase C, PKC; and calmodulin kinase, Ca(2+)-CaM), and Ca2+ by itself. The effects of activators are often highly synergistic or conditional, suggesting function of ACs as coincidence detectors. The plethora of G-protein-coupled receptors, together with functional differentiation among G-protein subunits and many AC isoforms, permits assembly of a very complex signaling systems with a wide variety of integrative characteristics. This survey presents basic facts on ACs classification and characteristics, and gives a brief review of the recent developments in this important and rapidly growing field of cyclic AMP research.