Choreographing the adenylyl cyclase signalosome: sorting out the partners and the steps

Abstract

Adenylyl cyclases are a ubiquitous family of enzymes and are critical regulators of metabolic and cardiovascular function. Multiple isoforms of the enzyme are expressed in a range of tissues. However, for many processes, the adenylyl cyclase isoforms have been thought of as essentially interchangeable, with their impact more dependent on their common actions to increase intracellular cyclic adenosine monophosphate content regardless of the isoform involved. It has long been appreciated that each subfamily of isoforms demonstrate a specific pattern of "upstream" regulation, i.e., specific patterns of ion dependence (e.g., calcium-dependence) and specific patterns of regulation by kinases (protein kinase A (PKA), protein kinase C (PKC), raf). However, more recent studies have suggested that adenylyl cyclase isoform-selective patterns of signaling are a wide-spread phenomenon. The determinants of these selective signaling patterns relate to a number of factors, including: (1) selective coupling of specific adenylyl cyclase isoforms with specific G protein-coupled receptors, (2) localization of specific adenylyl cyclase isoforms in defined structural domains (AKAP complexes, caveolin/lipid rafts), and (3) selective coupling of adenylyl cyclase isoforms with specific downstream signaling cascades important in regulation of cell growth and contractility. The importance of isoform-specific regulation has now been demonstrated both in mouse models as well as in humans. Adenylyl cyclase has not been viewed as a useful target for therapeutic regulation, given the ubiquitous expression of the enzyme and the perceived high risk of off-target effects. Understanding which isoforms of adenylyl cyclase mediate distinct cellular effects would bring new significance to the development of isoform-specific ligands to regulate discrete cellular actions.

Genome-wide association study reveals two new risk loci for bipolar disorder

“…The ADCY2 gene on chromosome 5p15.31 is expressed in the brain and encodes a cell membrane-bound enzyme for the synthesis of the second-messenger molecule cAMP. The ADCY2 protein is primarily regulated by heterotrimeric G proteins and produces cAMP in response to extracellular hormones and neurotransmitters that bind as ligands to G protein-coupled receptors (GPCRs) 23 . ADCY2 is also regulated by the protein kinase C (PKC) and the RAF kinase.…”

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

“…They can bind to AC to regulate cAMP synthesis and sequester phosphodiesterases to break down this second messenger locally. In addition, they tether PKA to specific subcellular sites, thereby focusing the activity of PKA toward relevant substrates (7,52). In vascular SMCs, studies have shown that the AKAP complex regulates specific vascular SMC functions, such as inhibition of cell migration, by causing localized changes in actin dynamics and reduction in cell proliferation and neointimal hyperplasia by stimulating cAMP-induced transcription and increasing the levels of the cyclin-dependent kinase-2 inhibitor p27kip1 (30,59).…”

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

“…As shown in Figure 12, when activated by ligandreceptor interaction, Gα s activates the closely associated adenylyl cyclase (AC), an enzyme that rapidly catalyzes the formation of cyclic AMP (cAMP) from ATP. Within the AC family of proteins, nine isoforms have been identified, and the effects of those isoforms are dependent on "signalosomes" recruited by each specific isoform 130 . As studied in the rat nephron, AC isoforms II, III, VI, VII, and IX are expressed in the proximal tubule, with II, III, and IX confirmed through IHC to be expressed only in the apical membrane (IHC data unavailable for VI and VII) 131 .…”