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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

Canonical Regulation of GPCR signaling by RGS proteins. Agonist binding to G protein-coupled receptors (GPCRs) induces a conformational change that facilitates the exchange of GDP for GTP on the α subunit of the heterotrimeric complex. Both GTP-bound Gα in the active form and the released Gβγ dimer can then go on to stimulate a number of downstream effectors. RGS proteins are GTPase accelerating proteins (GAPs) for Gα, which function to terminate signaling through GPCRs by accelerating the intrinsic GTPase activity of Gα and promoting re-association of the heterotrimeric complex with the receptor at the cell membrane.
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Figure 1: Canonical Regulation of GPCR signaling by RGS proteins. Agonist binding to G protein-coupled receptors (GPCRs) induces a conformational change that facilitates the exchange of GDP for GTP on the α subunit of the heterotrimeric complex. Both GTP-bound Gα in the active form and the released Gβγ dimer can then go on to stimulate a number of downstream effectors. RGS proteins are GTPase accelerating proteins (GAPs) for Gα, which function to terminate signaling through GPCRs by accelerating the intrinsic GTPase activity of Gα and promoting re-association of the heterotrimeric complex with the receptor at the cell membrane.

Mentions: The magnitude and duration of GPCR effector responses is limited by members of the regulator of G protein signaling (RGS) family of proteins, which act as GTPase accelerating proteins (GAPs) for Gα. By stabilizing the transition state of Gα in GTP hydrolysis, RGS proteins accelerate their intrinsic GTPase activity to facilitate termination of both Gα- and Gβγ-mediated cellular signaling (Figure 1). Twenty canonical RGS proteins, divided into four subfamilies based on sequence homology and the presence and nature of additional non-RGS domains, act as functional GAPs for Gαi/o, Gαq/11, or both (Table 1). Many of these proteins are detectable at the mRNA level in SAN, AVN, atria, or ventricles (Table 1), but lack of specific antibodies with corresponding genetic knockout controls has made detection of endogenous RGS proteins difficult in vivo, making investigations into the physiological significance of RGS proteins in the heart even more challenging. In fact, only RGS2, 3, 4, 5, and 6 have been detected at the protein level in heart (Table 1). Furthermore, physiological functions have only been attributed to a handful of RGS proteins in the heart and vasculature. Among these, RGS2 is a key regulator of vascular smooth muscle cell contractility and control of blood pressure (Heximer et al., 2003; Tang et al., 2003) and both RGS2 and RGS5 have been implicated as key inhibitors of cardiac hypertrophy and fibrosis in response to pressure overload (Takimoto et al., 2009; Li et al., 2010; Zhang et al., 2011).


RGS Proteins in Heart: Brakes on the Vagus.

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

Canonical Regulation of GPCR signaling by RGS proteins. Agonist binding to G protein-coupled receptors (GPCRs) induces a conformational change that facilitates the exchange of GDP for GTP on the α subunit of the heterotrimeric complex. Both GTP-bound Gα in the active form and the released Gβγ dimer can then go on to stimulate a number of downstream effectors. RGS proteins are GTPase accelerating proteins (GAPs) for Gα, which function to terminate signaling through GPCRs by accelerating the intrinsic GTPase activity of Gα and promoting re-association of the heterotrimeric complex with the receptor at the cell membrane.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368389&req=5

Figure 1: Canonical Regulation of GPCR signaling by RGS proteins. Agonist binding to G protein-coupled receptors (GPCRs) induces a conformational change that facilitates the exchange of GDP for GTP on the α subunit of the heterotrimeric complex. Both GTP-bound Gα in the active form and the released Gβγ dimer can then go on to stimulate a number of downstream effectors. RGS proteins are GTPase accelerating proteins (GAPs) for Gα, which function to terminate signaling through GPCRs by accelerating the intrinsic GTPase activity of Gα and promoting re-association of the heterotrimeric complex with the receptor at the cell membrane.
Mentions: The magnitude and duration of GPCR effector responses is limited by members of the regulator of G protein signaling (RGS) family of proteins, which act as GTPase accelerating proteins (GAPs) for Gα. By stabilizing the transition state of Gα in GTP hydrolysis, RGS proteins accelerate their intrinsic GTPase activity to facilitate termination of both Gα- and Gβγ-mediated cellular signaling (Figure 1). Twenty canonical RGS proteins, divided into four subfamilies based on sequence homology and the presence and nature of additional non-RGS domains, act as functional GAPs for Gαi/o, Gαq/11, or both (Table 1). Many of these proteins are detectable at the mRNA level in SAN, AVN, atria, or ventricles (Table 1), but lack of specific antibodies with corresponding genetic knockout controls has made detection of endogenous RGS proteins difficult in vivo, making investigations into the physiological significance of RGS proteins in the heart even more challenging. In fact, only RGS2, 3, 4, 5, and 6 have been detected at the protein level in heart (Table 1). Furthermore, physiological functions have only been attributed to a handful of RGS proteins in the heart and vasculature. Among these, RGS2 is a key regulator of vascular smooth muscle cell contractility and control of blood pressure (Heximer et al., 2003; Tang et al., 2003) and both RGS2 and RGS5 have been implicated as key inhibitors of cardiac hypertrophy and fibrosis in response to pressure overload (Takimoto et al., 2009; Li et al., 2010; Zhang et al., 2011).

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