At least nine closely related isoforms of adenylyl cyclases (ACs), the enzymes responsible for the synthesis of cyclic AMP (cAMP) from ATP, have been cloned and characterized in mammals. Depending on the properties and the relative levels of the isoforms expressed in a tissue or a cell type at a specific time, extracellular signals received through the G-protein-coupled receptors can be differentially integrated. The present review deals with various aspects of such regulations, emphasizing the role of calcium/calmodulin in activating AC1 and AC8 in the central nervous system, the potential inhibitory effect of calcium on AC5 and AC6, and the changes in the expression pattern of the isoforms during development. A particular emphasis is given to the role of cAMP during drug and ethanol dependency and to some experimental limitations (pitfalls in the interpretation of cellular transfection, scarcity of the invalidation models, existence of complex macromolecular structures, etc).

Regulation and Role of Adenylyl Cyclase Isoforms

Cyclic AMP is a universal second messenger, produced by a family of adenylyl cyclase (AC) enzymes. The last three decades have brought a wealth of new information about the regulation of cyclic AMP production by ACs. Nine hormone-sensitive, membrane-bound AC isoforms have been identified in addition to a tenth isoform that lacks membrane spans and more closely resembles the cyanobacterial AC enzymes. New model systems for purifying and characterizing the catalytic domains of AC have led to the crystal structure of these domains and the mapping of numerous interaction sites. However, big hurdles remain in unraveling the roles of individual AC isoforms and their regulation in physiological systems. In this review we explore the latest on AC knockout and overexpression studies to better understand the roles of G protein regulation of ACs in the brain, olfactory bulb, and heart.

/pdf/physiological-roles-for-g-protein-regulated-adenylyl-cyclase-qio15rhc8r.pdf

Physiological roles for G protein-regulated adenylyl cyclase isoforms: insights from knockout and overexpression studies.

A current challenge in cellular signaling is to decipher the complex intracellular spatiotemporal organization that any given cell type has developed to discriminate among different external stimuli acting via a common signaling pathway. This obviously applies to cAMP and cGMP signaling in the heart, where these cyclic nucleotides determine the regulation of cardiac function by many hormones and neuromediators. Recent studies have identified cyclic nucleotide phosphodiesterases as key actors in limiting the spread of cAMP and cGMP, and in shaping and organizing intracellular signaling microdomains. With this new role, phosphodiesterases have been promoted from the rank of a housekeeping attendant to that of an executive officer.

Compartmentation of Cyclic Nucleotide Signaling in the Heart The Role of Cyclic Nucleotide Phosphodiesterases

Beta-adrenergic receptor (AR) subtypes are archetypical members of the G protein-coupled receptor (GPCR) superfamily. Whereas both beta1AR and beta2AR stimulate the classic G(s)-adenylyl cyclase-3',5'-adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling cascade, beta2AR couples to both G(s) and G(i) proteins, activating bifurcated signaling pathways. In the heart, dual coupling of the beta2AR to G(s) and G(i) results in compartmentalization of the G(s)-stimulated cAMP signal, thus selectively affecting plasma membrane effectors (such as L-type Ca(2+) channels) and bypassing cytoplasmic target proteins (such as phospholamban and myofilament contractile proteins). More important, the beta2AR-to-G(i) branch delivers a powerful cell survival signal that counters apoptosis induced by the concurrent G(s)-mediated signal or by a wide range of assaulting factors. This survival pathway sequentially involves G(i), G(beta)(gamma), phosphoinositide 3-kinase, and Akt. Furthermore, cardiac-specific transgenic overexpression of betaAR subtypes in mice results in distinctly different phenotypes in terms of the likelihood of cardiac hypertrophy and heart failure. These findings indicate that stimulation of the two betaAR subtypes activates overlapping, but different, sets of signal transduction mechanisms, and fulfills distinct or even opposing physiological and pathophysiological roles. Because of these differences, selective activation of cardiac beta2AR may provide catecholamine-dependent inotropic support without cardiotoxic consequences, which might have beneficial effects in the failing heart.

/pdf/beta-adrenergic-signaling-in-the-heart-dual-coupling-of-the-rtey9pjgqp.pdf

Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G(s) and G(i) proteins.

https://digitalcommons.chapman.edu/cgi/viewcontent.cgi?article=1376&context=pharmacy_articles

Receptor Number and Caveolar Co-localization Determine Receptor Coupling Efficiency to Adenylyl Cyclase *

The limiting element in beta-adrenergic receptor (betaAR)-G(s)-adenylyl cyclase (AC) signal transduction in the cardiomyocyte is not known, but it has been proposed that the level of adenylyl cyclase expression constrains betaAR signaling. To alter the above equilibrium, type V AC was overexpressed in a myocyte-specific manner in the hearts of transgenic mice using the alpha-myosin heavy chain promoter. Expression of type V AC was approximately 75% over endogenous levels as quantitated by [(3)H]forskolin binding. Functional activity of the transgene product was evident in cardiac membrane AC studies, where basal (45 +/- 11 vs 19 +/- 5 pmol min(-)(1) mg(-)(1)) and forskolin+Mn(2+) (695 +/- 104 vs 386 +/- 34 pmol min(-)(1) mg(-)(1)) stimulated activities were increased compared to activities in nontransgenic (NTG) littermates. However, while isoproterenol stimulated activities were higher (74 +/- 12 vs 46 +/- 9.8 pmol min(-)(1) mg(-)(1)), the fold stimulation over basal was not increased in ACV overexpressors compared to NTG (line 14.3 = 2.29 +/- 0.44-fold, line 15.1 = 1.70 +/- 0.1-fold, NTG = 2.62 +/- 0.18-fold). Similarly, in whole cell patch-clamp studies, betaAR-mediated opening of L-type Ca(2+) channels was not found to be enhanced in transgenic ACV myocytes (225 +/- 15 vs 216 +/- 10% of basal currents). Basal and isoproterenol stimulated PKA activities were elevated in the ACV mice compared to NTG, but again the extent of stimulation over basal was not enhanced. Phosphorylated phospholamban was approximately 2-fold greater in myocytes from ACV hearts compared to NTG, indicating that distal elements of the contractile cascade are activated by AC overexpression. ACV mice displayed increased heart rates and fractional shortening as assessed by echocardiography. However, in vivo hemodynamic studies revealed that heart rate and contractility responses to agonist infusion were not enhanced in ACV mice compared to NTG. We conclude that at native stoichiometries, the levels of adenylyl cyclase influence basal activities and cardiac function, but do not constrain betaAR signaling in the cardiomyocyte.

Altering the receptor-effector ratio by transgenic overexpression of type V adenylyl cyclase: enhanced basal catalytic activity and function without increased cardiomyocyte beta-adrenergic signalling.

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Altering the receptor-effector ratio by transgenic overexpression of type V adenylyl cyclase: enhanced basal catalytic activity and function without increased cardiomyocyte beta-adrenergic signalling.