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RGS Proteins in Heart: Brakes on the Vagus.

Stewart A, Huang J, Fisher RA - Front Physiol (2012)

Bottom Line: However, expression of M2R-GIRK signaling components in heterologous systems failed to recapitulate native channel gating kinetics.The missing link was identified with the discovery of regulator of G protein signaling (RGS) proteins, which act as GTPase-activating proteins to accelerate the intrinsic GTPase activity of Gα resulting in termination of Gα- and Gβγ-mediated signaling to downstream effectors.Together, these studies identify RGS proteins, especially RGS6, as new therapeutic targets for diseases such as sick sinus syndrome or other maladies involving abnormal autonomic control of the heart.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Carver College of Medicine, University of Iowa Iowa City, IA, USA.

ABSTRACT
It has been nearly a century since Otto Loewi discovered that acetylcholine (ACh) release from the vagus produces bradycardia and reduced cardiac contractility. It is now known that parasympathetic control of the heart is mediated by ACh stimulation of G(i/o)-coupled muscarinic M2 receptors, which directly activate G protein-coupled inwardly rectifying potassium (GIRK) channels via Gβγ resulting in membrane hyperpolarization and inhibition of action potential (AP) firing. However, expression of M2R-GIRK signaling components in heterologous systems failed to recapitulate native channel gating kinetics. The missing link was identified with the discovery of regulator of G protein signaling (RGS) proteins, which act as GTPase-activating proteins to accelerate the intrinsic GTPase activity of Gα resulting in termination of Gα- and Gβγ-mediated signaling to downstream effectors. Studies in mice expressing an RGS-insensitive Gα(i2) mutant (G184S) implicated endogenous RGS proteins as key regulators of parasympathetic signaling in heart. Recently, two RGS proteins have been identified as critical regulators of M2R signaling in heart. RGS6 exhibits a uniquely robust expression in heart, especially in sinoatrial (SAN) and atrioventricular nodal regions. Mice lacking RGS6 exhibit increased bradycardia and inhibition of SAN AP firing in response to CCh as well as a loss of rapid activation and deactivation kinetics and current desensitization for ACh-induced GIRK current (I(KACh)). Similar findings were observed in mice lacking RGS4. Thus, dysregulation in RGS protein expression or function may contribute to pathologies involving aberrant electrical activity in cardiac pacemaker cells. Moreover, RGS6 expression was found to be up-regulated in heart under certain pathological conditions, including doxorubicin treatment, which is known to cause life-threatening cardiotoxicity and atrial fibrillation in cancer patients. On the other hand, increased vagal tone may be cardioprotective in heart failure where acetylcholinesterase inhibitors and vagal stimulation have been proposed as potential therapeutics. Together, these studies identify RGS proteins, especially RGS6, as new therapeutic targets for diseases such as sick sinus syndrome or other maladies involving abnormal autonomic control of the heart.

No MeSH data available.


Related in: MedlinePlus

Regulator of G protein signaling-mediated regulation of cardiac automaticity in atrial myocytes. In atrial myocytes, Gs-coupled β1- or β2-adrenergic receptors (β1/2AR) stimulate adenylate cyclase-mediated production of the second messenger cyclic AMP (cAMP), activation of cAMP-dependent protein kinase (PKA), and induction of the calcium current (ICa,L) through L-type calcium channels (primarily Cav1.2). The net effect is membrane depolarization, increased cell excitation, and enhanced cardiac contractility. Adenylate cyclase is inhibited by Gαi/o-coupled muscarinic M2 receptors (M2R), and activated M2Rs can also directly induce G protein-coupled inwardly rectifying potassium channel (GIRK) current (IKACh) via Gβγ resulting in membrane hyperpolarization and inhibition of cell firing. β2ARs can also couple to Gαi/o in these cells and block AC-mediated cAMP production. Adenosine A1 receptors (A1R) also have a negative chronotropic effect in atrial myocytes via Gαo-dependent inhibition of ICa,L, though the exact mechanism whereby this occurs remains unclear. RGS6 functions to inactivate stimulated M2Rs and block subsequent GIRK current (IKACh) in atrial myocytes. The specific RGS protein(s) regulating A1Rs and Gαi/o-coupled β2AR in this tissue have yet to be identified.
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Figure 3: Regulator of G protein signaling-mediated regulation of cardiac automaticity in atrial myocytes. In atrial myocytes, Gs-coupled β1- or β2-adrenergic receptors (β1/2AR) stimulate adenylate cyclase-mediated production of the second messenger cyclic AMP (cAMP), activation of cAMP-dependent protein kinase (PKA), and induction of the calcium current (ICa,L) through L-type calcium channels (primarily Cav1.2). The net effect is membrane depolarization, increased cell excitation, and enhanced cardiac contractility. Adenylate cyclase is inhibited by Gαi/o-coupled muscarinic M2 receptors (M2R), and activated M2Rs can also directly induce G protein-coupled inwardly rectifying potassium channel (GIRK) current (IKACh) via Gβγ resulting in membrane hyperpolarization and inhibition of cell firing. β2ARs can also couple to Gαi/o in these cells and block AC-mediated cAMP production. Adenosine A1 receptors (A1R) also have a negative chronotropic effect in atrial myocytes via Gαo-dependent inhibition of ICa,L, though the exact mechanism whereby this occurs remains unclear. RGS6 functions to inactivate stimulated M2Rs and block subsequent GIRK current (IKACh) in atrial myocytes. The specific RGS protein(s) regulating A1Rs and Gαi/o-coupled β2AR in this tissue have yet to be identified.

Mentions: Two RGS proteins, RGS6 and RGS4, have recently been identified as critical negative regulators of M2R signaling in heart, functioning to set the parasympathetic “tone” by acting as the brake on vagal stimulation of the heart (Figures 2 and 3). It remains unclear, however, whether RGS6 and RGS4 are redundant inactivators of cardiac M2R signaling or if they cooperate to ensure proper parasympathetic control of HR by regulating distinct channel, GPCR, or G protein populations or by functioning in different cardiac cells. Nevertheless, dysregulation in the expression of either RGS6 or RGS4 could contribute to the loss of vagal tone observed in cardiovascular diseases. Complete and comprehensive understanding of the role of RGS proteins in regulating parasympathetic stimulation of the heart could lead to the development of novel treatment strategies for cardiac pathologies involving arrhythmias and conduction defects that result from unchecked parasympathetic signaling. Among these are pathological AV block, sick sinus syndrome, and arrhythmias (Fu et al., 2007). Considering the cardioprotective effect of increased vagal tone, these RGS proteins are also being considered as viable druggable targets in the treatment of heart failure and doxorubicin-induced cardiotoxicity.


RGS Proteins in Heart: Brakes on the Vagus.

Stewart A, Huang J, Fisher RA - Front Physiol (2012)

Regulator of G protein signaling-mediated regulation of cardiac automaticity in atrial myocytes. In atrial myocytes, Gs-coupled β1- or β2-adrenergic receptors (β1/2AR) stimulate adenylate cyclase-mediated production of the second messenger cyclic AMP (cAMP), activation of cAMP-dependent protein kinase (PKA), and induction of the calcium current (ICa,L) through L-type calcium channels (primarily Cav1.2). The net effect is membrane depolarization, increased cell excitation, and enhanced cardiac contractility. Adenylate cyclase is inhibited by Gαi/o-coupled muscarinic M2 receptors (M2R), and activated M2Rs can also directly induce G protein-coupled inwardly rectifying potassium channel (GIRK) current (IKACh) via Gβγ resulting in membrane hyperpolarization and inhibition of cell firing. β2ARs can also couple to Gαi/o in these cells and block AC-mediated cAMP production. Adenosine A1 receptors (A1R) also have a negative chronotropic effect in atrial myocytes via Gαo-dependent inhibition of ICa,L, though the exact mechanism whereby this occurs remains unclear. RGS6 functions to inactivate stimulated M2Rs and block subsequent GIRK current (IKACh) in atrial myocytes. The specific RGS protein(s) regulating A1Rs and Gαi/o-coupled β2AR in this tissue have yet to be identified.
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Related In: Results  -  Collection

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Figure 3: Regulator of G protein signaling-mediated regulation of cardiac automaticity in atrial myocytes. In atrial myocytes, Gs-coupled β1- or β2-adrenergic receptors (β1/2AR) stimulate adenylate cyclase-mediated production of the second messenger cyclic AMP (cAMP), activation of cAMP-dependent protein kinase (PKA), and induction of the calcium current (ICa,L) through L-type calcium channels (primarily Cav1.2). The net effect is membrane depolarization, increased cell excitation, and enhanced cardiac contractility. Adenylate cyclase is inhibited by Gαi/o-coupled muscarinic M2 receptors (M2R), and activated M2Rs can also directly induce G protein-coupled inwardly rectifying potassium channel (GIRK) current (IKACh) via Gβγ resulting in membrane hyperpolarization and inhibition of cell firing. β2ARs can also couple to Gαi/o in these cells and block AC-mediated cAMP production. Adenosine A1 receptors (A1R) also have a negative chronotropic effect in atrial myocytes via Gαo-dependent inhibition of ICa,L, though the exact mechanism whereby this occurs remains unclear. RGS6 functions to inactivate stimulated M2Rs and block subsequent GIRK current (IKACh) in atrial myocytes. The specific RGS protein(s) regulating A1Rs and Gαi/o-coupled β2AR in this tissue have yet to be identified.
Mentions: Two RGS proteins, RGS6 and RGS4, have recently been identified as critical negative regulators of M2R signaling in heart, functioning to set the parasympathetic “tone” by acting as the brake on vagal stimulation of the heart (Figures 2 and 3). It remains unclear, however, whether RGS6 and RGS4 are redundant inactivators of cardiac M2R signaling or if they cooperate to ensure proper parasympathetic control of HR by regulating distinct channel, GPCR, or G protein populations or by functioning in different cardiac cells. Nevertheless, dysregulation in the expression of either RGS6 or RGS4 could contribute to the loss of vagal tone observed in cardiovascular diseases. Complete and comprehensive understanding of the role of RGS proteins in regulating parasympathetic stimulation of the heart could lead to the development of novel treatment strategies for cardiac pathologies involving arrhythmias and conduction defects that result from unchecked parasympathetic signaling. Among these are pathological AV block, sick sinus syndrome, and arrhythmias (Fu et al., 2007). Considering the cardioprotective effect of increased vagal tone, these RGS proteins are also being considered as viable druggable targets in the treatment of heart failure and doxorubicin-induced cardiotoxicity.

Bottom Line: However, expression of M2R-GIRK signaling components in heterologous systems failed to recapitulate native channel gating kinetics.The missing link was identified with the discovery of regulator of G protein signaling (RGS) proteins, which act as GTPase-activating proteins to accelerate the intrinsic GTPase activity of Gα resulting in termination of Gα- and Gβγ-mediated signaling to downstream effectors.Together, these studies identify RGS proteins, especially RGS6, as new therapeutic targets for diseases such as sick sinus syndrome or other maladies involving abnormal autonomic control of the heart.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Carver College of Medicine, University of Iowa Iowa City, IA, USA.

ABSTRACT
It has been nearly a century since Otto Loewi discovered that acetylcholine (ACh) release from the vagus produces bradycardia and reduced cardiac contractility. It is now known that parasympathetic control of the heart is mediated by ACh stimulation of G(i/o)-coupled muscarinic M2 receptors, which directly activate G protein-coupled inwardly rectifying potassium (GIRK) channels via Gβγ resulting in membrane hyperpolarization and inhibition of action potential (AP) firing. However, expression of M2R-GIRK signaling components in heterologous systems failed to recapitulate native channel gating kinetics. The missing link was identified with the discovery of regulator of G protein signaling (RGS) proteins, which act as GTPase-activating proteins to accelerate the intrinsic GTPase activity of Gα resulting in termination of Gα- and Gβγ-mediated signaling to downstream effectors. Studies in mice expressing an RGS-insensitive Gα(i2) mutant (G184S) implicated endogenous RGS proteins as key regulators of parasympathetic signaling in heart. Recently, two RGS proteins have been identified as critical regulators of M2R signaling in heart. RGS6 exhibits a uniquely robust expression in heart, especially in sinoatrial (SAN) and atrioventricular nodal regions. Mice lacking RGS6 exhibit increased bradycardia and inhibition of SAN AP firing in response to CCh as well as a loss of rapid activation and deactivation kinetics and current desensitization for ACh-induced GIRK current (I(KACh)). Similar findings were observed in mice lacking RGS4. Thus, dysregulation in RGS protein expression or function may contribute to pathologies involving aberrant electrical activity in cardiac pacemaker cells. Moreover, RGS6 expression was found to be up-regulated in heart under certain pathological conditions, including doxorubicin treatment, which is known to cause life-threatening cardiotoxicity and atrial fibrillation in cancer patients. On the other hand, increased vagal tone may be cardioprotective in heart failure where acetylcholinesterase inhibitors and vagal stimulation have been proposed as potential therapeutics. Together, these studies identify RGS proteins, especially RGS6, as new therapeutic targets for diseases such as sick sinus syndrome or other maladies involving abnormal autonomic control of the heart.

No MeSH data available.


Related in: MedlinePlus