Biological roles of cAMP: variations on a theme in the different kingdoms of life

Abstract

Cyclic AMP (cAMP) plays a key regulatory role in most types of cells; however, the pathways controlled by cAMP may present important differences between organisms and between tissues within a specific organism. Changes in cAMP levels are caused by multiple triggers, most affecting adenylyl cyclases, the enzymes that synthesize cAMP. Adenylyl cyclases form a large and diverse family including soluble forms and others with one or more transmembrane domains. Regulatory mechanisms for the soluble adenylyl cyclases involve either interaction with diverse proteins, as happens in Escherichia coli or yeasts, or with calcium or bicarbonate ions, as occurs in mammalian cells. The transmembrane cyclases can be regulated by a variety of proteins, among which the α subunit and the βγ complex from G proteins coupled to membrane receptors are prominent. cAMP levels also are controlled by the activity of phosphodiesterases, enzymes that hydrolyze cAMP. Phosphodiesterases can be regulated by cAMP, cGMP or calcium‐calmodulin or by phosphorylation by different protein kinases. Regulation through cAMP depends on its binding to diverse proteins, its proximal targets, this in turn causing changes in a variety of distal targets. Specifically, binding of cAMP to regulatory subunits of cAMP‐dependent protein kinases (PKAs) affects the activity of substrates of PKA, binding to exchange proteins directly activated by cAMP (Epac) regulates small GTPases, binding to transcription factors such as the cAMP receptor protein (CRP) or the virulence factor regulator (Vfr) modifies the rate of transcription of certain genes, while cAMP binding to ion channels modulates their activity directly. Further studies on cAMP signalling will have important implications, not only for advancing fundamental knowledge but also for identifying targets for the development of new therapeutic agents.

Regulation of Mitochondrial Poly(ADP-Ribose) Polymerase Activation by theβ-Adrenoceptor/cAMP/Protein Kinase A Axis during Oxidative Stress

“…(Masmoudi et al, 1988;Du et al, 2003;Rossi et al, 2009). Based on the results of the PLA assays, we conclude that the mitochondrial PARP1 activation is an early event in oxidant-induced cell injury and, in line with the extranuclear/mitochondrial localization of PKA (Gancedo, 2013;Taylor et al, 2013;Valsecchi et al, 2013), the PKA/PARP1 interactions primarily occur in the extranuclear/mitochondrial compartment. The current findings are consistent with prior studies demonstrating the stimulation of mitochondrial PKA activity by treatment of the cells with b-receptor ligands such as isoproterenol (Lefkimmiatis et al, 2013) and are also consistent with prior data showing the direct regulation of mitochondrial PKA activity by cytosolic cAMP (Lefkimmiatis et al, 2013).…”

“…7A). The functionality of the b-adrenergic receptor on the cells was confirmed by measuring cAMP levels, the primary second messenger of b-adrenoceptor signaling (Gancedo, 2013;Taylor et al, 2013;Valsecchi et al, 2013). In line with prior observations (Chen et al, 1993; Lopez-Hellin et al, 1998), oxidative stress decreased cAMP levels in U937; cAMP levels were further reduced by propranolol, while they were increased by isoproterenol (Fig.…”

“…Protein kinase A (PKA), a cyclic adenosine monophosphate (cAMP)-dependent serine/threonine kinase, is one of the major effector proteins of cAMP and a regulator of cellular function in health and disease (Gancedo, 2013;Taylor et al, 2013;Valsecchi et al, 2013). The purpose of the current study was to determine whether PARP1 activity is regulated by the b-adrenoceptor/cAMP/PKA system during oxidative stress.…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…ACs are broadly expressed in the kingdom of life (Linder and Schultz, 2003;Gancedo, 2013). This IUPHAR review exclusively covers mammalian ACs and focuses on the nine membrane AC isoforms, AC1-AC9 (Alexander et al, 2015; http://www.guidetopharmacology.org/GRAC/ FamilyDisplayForward?familyId=257).…”

Structural and Biochemical Analysis of the Essential Diadenylate Cyclase CdaA from Listeria monocytogenes

“…The functions of cAMP, (p)ppGpp, and c-di-GMP have been studied extensively in several bacteria (3)(4)(5). However, fascinating novel discoveries (e.g.…”