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Cardiac cAMP: production, hydrolysis, modulation and detection.

Boularan C, Gales C - Front Pharmacol (2015)

Bottom Line: Cyclic adenosine 3',5'-monophosphate (cAMP) modulates a broad range of biological processes including the regulation of cardiac myocyte contractile function where it constitutes the main second messenger for β-adrenergic receptors' signaling to fulfill positive chronotropic, inotropic and lusitropic effects.A growing number of studies pinpoint the role of spatial organization of the cAMP signaling as an essential mechanism to regulate cAMP outcomes in cardiac physiology.Here, we will briefly discuss the complexity of cAMP synthesis and degradation in the cardiac context, describe the way to detect it and review the main pharmacological arsenal to modulate its availability.

View Article: PubMed Central - PubMed

Affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier Toulouse, France.

ABSTRACT
Cyclic adenosine 3',5'-monophosphate (cAMP) modulates a broad range of biological processes including the regulation of cardiac myocyte contractile function where it constitutes the main second messenger for β-adrenergic receptors' signaling to fulfill positive chronotropic, inotropic and lusitropic effects. A growing number of studies pinpoint the role of spatial organization of the cAMP signaling as an essential mechanism to regulate cAMP outcomes in cardiac physiology. Here, we will briefly discuss the complexity of cAMP synthesis and degradation in the cardiac context, describe the way to detect it and review the main pharmacological arsenal to modulate its availability.

No MeSH data available.


AKAP-dependent AC and PDE compartmentalizations in the cardiomyocyte. Abbreviations stand for: AKAP, A-kinase anchor proteins; PKA, Protein Kinase A; β2AR/β1AR, beta adrenergic receptor; PLN, Phospholamban; EPAC, cAMP-dependent exchange proteins; AC, Adenylyl cyclase; RyR, Ryanodine Receptor; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; KCNQ1, potassium channel voltage gated KQT-like subfamily Q; PDE, Phosphodiesterase; T-tubule, Transverse tubule; LTCC, L-type calcium channel.
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Figure 2: AKAP-dependent AC and PDE compartmentalizations in the cardiomyocyte. Abbreviations stand for: AKAP, A-kinase anchor proteins; PKA, Protein Kinase A; β2AR/β1AR, beta adrenergic receptor; PLN, Phospholamban; EPAC, cAMP-dependent exchange proteins; AC, Adenylyl cyclase; RyR, Ryanodine Receptor; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; KCNQ1, potassium channel voltage gated KQT-like subfamily Q; PDE, Phosphodiesterase; T-tubule, Transverse tubule; LTCC, L-type calcium channel.

Mentions: Adenylyl cyclases (AC) are ubiquitous enzymes that catalyze the conversion of Adenosine triphosphate (ATP) into cAMP and pyrophosphate. ACs structure consists in 12 transmembrane domains divided into 2 hydrophobics domains (6 transmembrane domains each) and 2 main intracellular loops called C1 and C2 that naturally dimerize to form the catalytic domain (Figure 1A). In mammals, 9 transmembrane and 1 soluble AC (sAC) encoded by different genes have been identified and have different regulatory mechanisms (Willoughby and Cooper, 2007). Mammalian ACs are strongly activated by Mn2+ or Mg2+ (Tesmer et al., 1999) and inhibited by millimolar concentrations of free Ca2+ probably acting as a Mg2+ competitor (Mou et al., 2009) but at submicromolar concentrations, Ca2+ can activate AC via calmodulin (CaM) throught its binding to a putative helical structure on the C1b region (Halls and Cooper, 2011). More precisely AC1, 3, and 8 are Ca2+/CaM sensitive isoforms which localize in lipid rafts while AC2, 4, 7, and 9 are Ca2+/CaM insensitive and are excluded from these membrane domains (Willoughby and Cooper, 2007). On the contrary, biochemical studies on membrane preparations revealed that AC5 and AC6 could be inhibited by Ca2+ (independently of CaM) in the submicromolar range (Guillou et al., 1999; Hu et al., 2002). Along with nitric oxide (NO), Hydrogen sulfide (H2S) is a biological gaseous transmitter able to modulate cAMP production. Using NO donors, the gasotransmitter NO is thought to attenuate forskolin-stimulated AC5 and AC6 isoforms activities without altering their basal activity on membrane from rat striatum (Hudson et al., 2001). Even if H2S is a poisonous gas used as a chemical reagent, H2S is endogenously formed in mammalian cells from cysteine by the action of cystathionine β-synthase with serine as a by-product at a concentration around 50–160 μmol/L (Goodwin et al., 1989). In the central nervous system, H2S enhances NMDA receptor-mediated response via cAMP production (Kimura, 2000) while in cardiac context it can also suppressed AC activity and, therefore, decreased forskolin-stimulated cAMP accumulation in different cell lines and tissue (Lim et al., 2008; Yong et al., 2008). In the cardiomyocytes, expression of AC1, AC5, AC6, AC8, and sAC has been detected and most function as modulators of inotropic and chronotropic β-adrenergic receptor (β-AR) signaling output (Table 1) but AC5 and AC6 represent the dominant isoform (Defer et al., 2000). Along with AC distribution within membrane microdomains (Efendiev and Dessauer, 2011), cAMP synthesis is spatially restricted by localization of activating receptors like β1-adrenergic receptors or β2-adrenergic receptors at caveolae or non-caveolae plasma membrane domains (Rybin et al., 2000; Ostrom et al., 2001). Moreover, specific A-kinase anchor proteins (AKAP) complexes (Kapiloff et al., 2014) have been identified as a potential molecular mechanism for the formation of specific cAMP microdomains (Kapiloff et al., 2014). The AKAPs constitute signaling hub proteins that scaffold on a same membrane domain the AC and the regulatory subunit of protein kinase A (PKA) cAMP effector, thus confining the enzyme activity to discrete locations within the cell. Cardiac myocytes exhibit at least four distinct AKAP complexes: AKAP79/150 (aka AKAP5) with AC5/6 (Nichols et al., 2010); mAKAPβ (aka AKAP6) with AC2/5 (Kapiloff et al., 2009), YOTIAO (aka AKAP9) with AC2/9 (Piggott et al., 2008), and AKAP18δ with PKA (Fraser et al., 1998) (Figure 2).


Cardiac cAMP: production, hydrolysis, modulation and detection.

Boularan C, Gales C - Front Pharmacol (2015)

AKAP-dependent AC and PDE compartmentalizations in the cardiomyocyte. Abbreviations stand for: AKAP, A-kinase anchor proteins; PKA, Protein Kinase A; β2AR/β1AR, beta adrenergic receptor; PLN, Phospholamban; EPAC, cAMP-dependent exchange proteins; AC, Adenylyl cyclase; RyR, Ryanodine Receptor; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; KCNQ1, potassium channel voltage gated KQT-like subfamily Q; PDE, Phosphodiesterase; T-tubule, Transverse tubule; LTCC, L-type calcium channel.
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Related In: Results  -  Collection

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Figure 2: AKAP-dependent AC and PDE compartmentalizations in the cardiomyocyte. Abbreviations stand for: AKAP, A-kinase anchor proteins; PKA, Protein Kinase A; β2AR/β1AR, beta adrenergic receptor; PLN, Phospholamban; EPAC, cAMP-dependent exchange proteins; AC, Adenylyl cyclase; RyR, Ryanodine Receptor; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; KCNQ1, potassium channel voltage gated KQT-like subfamily Q; PDE, Phosphodiesterase; T-tubule, Transverse tubule; LTCC, L-type calcium channel.
Mentions: Adenylyl cyclases (AC) are ubiquitous enzymes that catalyze the conversion of Adenosine triphosphate (ATP) into cAMP and pyrophosphate. ACs structure consists in 12 transmembrane domains divided into 2 hydrophobics domains (6 transmembrane domains each) and 2 main intracellular loops called C1 and C2 that naturally dimerize to form the catalytic domain (Figure 1A). In mammals, 9 transmembrane and 1 soluble AC (sAC) encoded by different genes have been identified and have different regulatory mechanisms (Willoughby and Cooper, 2007). Mammalian ACs are strongly activated by Mn2+ or Mg2+ (Tesmer et al., 1999) and inhibited by millimolar concentrations of free Ca2+ probably acting as a Mg2+ competitor (Mou et al., 2009) but at submicromolar concentrations, Ca2+ can activate AC via calmodulin (CaM) throught its binding to a putative helical structure on the C1b region (Halls and Cooper, 2011). More precisely AC1, 3, and 8 are Ca2+/CaM sensitive isoforms which localize in lipid rafts while AC2, 4, 7, and 9 are Ca2+/CaM insensitive and are excluded from these membrane domains (Willoughby and Cooper, 2007). On the contrary, biochemical studies on membrane preparations revealed that AC5 and AC6 could be inhibited by Ca2+ (independently of CaM) in the submicromolar range (Guillou et al., 1999; Hu et al., 2002). Along with nitric oxide (NO), Hydrogen sulfide (H2S) is a biological gaseous transmitter able to modulate cAMP production. Using NO donors, the gasotransmitter NO is thought to attenuate forskolin-stimulated AC5 and AC6 isoforms activities without altering their basal activity on membrane from rat striatum (Hudson et al., 2001). Even if H2S is a poisonous gas used as a chemical reagent, H2S is endogenously formed in mammalian cells from cysteine by the action of cystathionine β-synthase with serine as a by-product at a concentration around 50–160 μmol/L (Goodwin et al., 1989). In the central nervous system, H2S enhances NMDA receptor-mediated response via cAMP production (Kimura, 2000) while in cardiac context it can also suppressed AC activity and, therefore, decreased forskolin-stimulated cAMP accumulation in different cell lines and tissue (Lim et al., 2008; Yong et al., 2008). In the cardiomyocytes, expression of AC1, AC5, AC6, AC8, and sAC has been detected and most function as modulators of inotropic and chronotropic β-adrenergic receptor (β-AR) signaling output (Table 1) but AC5 and AC6 represent the dominant isoform (Defer et al., 2000). Along with AC distribution within membrane microdomains (Efendiev and Dessauer, 2011), cAMP synthesis is spatially restricted by localization of activating receptors like β1-adrenergic receptors or β2-adrenergic receptors at caveolae or non-caveolae plasma membrane domains (Rybin et al., 2000; Ostrom et al., 2001). Moreover, specific A-kinase anchor proteins (AKAP) complexes (Kapiloff et al., 2014) have been identified as a potential molecular mechanism for the formation of specific cAMP microdomains (Kapiloff et al., 2014). The AKAPs constitute signaling hub proteins that scaffold on a same membrane domain the AC and the regulatory subunit of protein kinase A (PKA) cAMP effector, thus confining the enzyme activity to discrete locations within the cell. Cardiac myocytes exhibit at least four distinct AKAP complexes: AKAP79/150 (aka AKAP5) with AC5/6 (Nichols et al., 2010); mAKAPβ (aka AKAP6) with AC2/5 (Kapiloff et al., 2009), YOTIAO (aka AKAP9) with AC2/9 (Piggott et al., 2008), and AKAP18δ with PKA (Fraser et al., 1998) (Figure 2).

Bottom Line: Cyclic adenosine 3',5'-monophosphate (cAMP) modulates a broad range of biological processes including the regulation of cardiac myocyte contractile function where it constitutes the main second messenger for β-adrenergic receptors' signaling to fulfill positive chronotropic, inotropic and lusitropic effects.A growing number of studies pinpoint the role of spatial organization of the cAMP signaling as an essential mechanism to regulate cAMP outcomes in cardiac physiology.Here, we will briefly discuss the complexity of cAMP synthesis and degradation in the cardiac context, describe the way to detect it and review the main pharmacological arsenal to modulate its availability.

View Article: PubMed Central - PubMed

Affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier Toulouse, France.

ABSTRACT
Cyclic adenosine 3',5'-monophosphate (cAMP) modulates a broad range of biological processes including the regulation of cardiac myocyte contractile function where it constitutes the main second messenger for β-adrenergic receptors' signaling to fulfill positive chronotropic, inotropic and lusitropic effects. A growing number of studies pinpoint the role of spatial organization of the cAMP signaling as an essential mechanism to regulate cAMP outcomes in cardiac physiology. Here, we will briefly discuss the complexity of cAMP synthesis and degradation in the cardiac context, describe the way to detect it and review the main pharmacological arsenal to modulate its availability.

No MeSH data available.