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Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
The adenylyl cyclases are variously regulated by G protein subunits, a number of serine/threonine and tyrosine protein kinases, and Ca2+. In some physiological situations, this regulation can be readily incorporated into a hormonal cascade, controlling processes such as cardiac contractility or neurotransmitter release. However, the significance of some modes of regulation is obscure and is likely only to be apparent in explicit cellular contexts (or stages of the cell cycle). The regulation of many of the ACs by the ubiquitous second messenger Ca2+ provides an overarching mechanism for integrating the activities of these two major signaling systems. Elaborate devices have been evolved to ensure that this interaction occurs, to guarantee the fidelity of the interaction, and to insulate the microenvironment in which it occurs. Subcellular targeting, as well as a variety of scaffolding devices, is used to promote interaction of the ACs with specific signaling proteins and regulatory factors to generate privileged domains for cAMP signaling. A direct consequence of this organization is that cAMP will exhibit distinct kinetics in discrete cellular domains. A variety of means are now available to study cAMP in these domains and to dissect their components in real time in live cells. These topics are explored within the present review.
2 The relevance of the similarity of properties of ACs and transporters may become more apparent when the issue of their sensitivity to Ca2+ entry is considered (see sect. V).
3 Even though only one ATP molecule is used per catalytic center of mammalian ACs, bacterial and metazoan ACs, which also possess two ATP binding domains, actually have two catalytic centers, which utilize two ATP molecules (228).
4 The reader is directed to reviews in References 30, 90, 180, and 365 for further detail, much of which is summarized in Table 1. It is important to recognize that certain of these type-specific observations have only been made in one or two sources, or with overexpressed proteins. Nevertheless, these enzymes are remarkably understudied, and the discovery of an appropriate context could render some of the apparently "minor" regulatory properties of major significance.
5 The numbering of these cDNAs was a little confused initially; AC6 was first described as AC5. Confusion as to which AC was in press first resulted in the "AC5" reported in Reference 422 being renamed as AC6.
6 More detail can be found in reviews specific to this area (e.g., Refs. 129, 294).
7 In this study, AC3 was also included; no effect of Ca2+ was observed.
8 The recent flurry of literature suggesting that the ER is recruited by the interaction of STIM1 and Orai1 at the plasma membrane (298, 356) as a consequence of depletion of intracellular Ca2+ stores is likely to have implications for the physical organization of the AC microdomain.
9 Native CNG channels are heteromers of 
- and 
-subunits. However, homomeric assemblies of -subunits form fully functional channels when expressed as sensors using an adenovirus system (320).
10 PCR suggests the presence of multiple ACs in tissue samples.
11 Specific inhibitors of the AC reaction have been developed that are based around the structure of forskolin, or ATP and related compounds (158, 287). Those currently available display a degree of selectivity for some AC species. Increasing their AC selectivity and their cell permeability would enhance their usefulness.
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