Endogenous RGS proteins modulate SA and AV nodal functions in isolated heart: implications for sick sinus syndrome and AV block. 2007

Ying Fu, and Xinyan Huang, and Lin Piao, and Anatoli N Lopatin, and Richard R Neubig
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109-0632, USA.

G protein-coupled receptors play a pivotal role in regulating cardiac automaticity. Their function is controlled by regulator of G protein signaling (RGS) proteins acting as GTPase-activating proteins for Galpha subunits to suppress Galpha(i) and Galpha(q) signaling. Using knock-in mice in which Galpha(i2)-RGS binding and negative regulation are disrupted by a genomic Galpha(i2)G184S (GS) point mutation, we recently (Fu Y, Huang X, Zhong H, Mortensen RM, D'Alecy LG, Neubig RR. Circ Res 98: 659-666, 2006) showed that endogenous RGS proteins suppress muscarinic receptor-mediated bradycardia. To determine whether this was due to direct regulation of cardiac pacemakers or to alterations in the central nervous system or vascular responses, we examined isolated, perfused hearts. Isoproterenol-stimulated beating rates of heterozygote (+/GS) and homozygote (GS/GS) hearts were significantly more sensitive to inhibition by carbachol than were those of wild type (+/+). Even greater effects were seen in the absence of isoproterenol; the potency of muscarinic-mediated bradycardia was enhanced fivefold in GS/GS and twofold in +/GS hearts compared with +/+. A(1)-adenosine receptor-mediated bradycardia was unaffected. In addition to effects on the sinoatrial node, +/GS and GS/GS hearts show significantly increased carbachol-induced third-degree atrioventricular (AV) block. Atrial pacing studies demonstrated an increased PR interval and AV effective refractory period in GS/GS hearts compared with +/+. Thus loss of the inhibitory action of endogenous RGS proteins on Galpha(i2) potentiates muscarinic inhibition of cardiac automaticity and conduction. The severe carbachol-induced sinus bradycardia in Galpha(i2)G184S mice suggests a possible role for alterations of Galpha(i2) or RGS proteins in sick sinus syndrome and pathological AV block.

UI MeSH Term Description Entries
D006327 Heart Block Impaired conduction of cardiac impulse that can occur anywhere along the conduction pathway, such as between the SINOATRIAL NODE and the right atrium (SA block) or between atria and ventricles (AV block). Heart blocks can be classified by the duration, frequency, or completeness of conduction block. Reversibility depends on the degree of structural or functional defects. Auriculo-Ventricular Dissociation,A-V Dissociation,Atrioventricular Dissociation,A V Dissociation,A-V Dissociations,Atrioventricular Dissociations,Auriculo Ventricular Dissociation,Auriculo-Ventricular Dissociations,Block, Heart,Blocks, Heart,Dissociation, A-V,Dissociation, Atrioventricular,Dissociation, Auriculo-Ventricular,Dissociations, A-V,Dissociations, Atrioventricular,Dissociations, Auriculo-Ventricular,Heart Blocks
D006339 Heart Rate The number of times the HEART VENTRICLES contract per unit of time, usually per minute. Cardiac Rate,Chronotropism, Cardiac,Heart Rate Control,Heartbeat,Pulse Rate,Cardiac Chronotropy,Cardiac Chronotropism,Cardiac Rates,Chronotropy, Cardiac,Control, Heart Rate,Heart Rates,Heartbeats,Pulse Rates,Rate Control, Heart,Rate, Cardiac,Rate, Heart,Rate, Pulse
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001283 Atrioventricular Node A small nodular mass of specialized muscle fibers located in the interatrial septum near the opening of the coronary sinus. It gives rise to the atrioventricular bundle of the conduction system of the heart. AV Node,A-V Node,Atrio-Ventricular Node,A V Node,A-V Nodes,AV Nodes,Atrio Ventricular Node,Atrio-Ventricular Nodes,Atrioventricular Nodes,Node, A-V,Node, AV,Node, Atrio-Ventricular,Node, Atrioventricular,Nodes, A-V,Nodes, AV,Nodes, Atrio-Ventricular,Nodes, Atrioventricular
D012804 Sick Sinus Syndrome A condition caused by dysfunctions related to the SINOATRIAL NODE including impulse generation (CARDIAC SINUS ARREST) and impulse conduction (SINOATRIAL EXIT BLOCK). It is characterized by persistent BRADYCARDIA, chronic ATRIAL FIBRILLATION, and failure to resume sinus rhythm following CARDIOVERSION. This syndrome can be congenital or acquired, particularly after surgical correction for heart defects. Sinus Node Dysfunction,Sick Sinus Node Syndrome,Sinus Node Disease,Dysfunction, Sinus Node,Dysfunctions, Sinus Node,Sinus Node Diseases,Syndrome, Sick Sinus
D012849 Sinoatrial Node The small mass of modified cardiac muscle fibers located at the junction of the superior vena cava (VENA CAVA, SUPERIOR) and right atrium. Contraction impulses probably start in this node, spread over the atrium (HEART ATRIUM) and are then transmitted by the atrioventricular bundle (BUNDLE OF HIS) to the ventricle (HEART VENTRICLE). Sinuatrial Node,Sinus Node,Sino-Atrial Node,Sinu-Atrial Node,Node, Sino-Atrial,Node, Sinoatrial,Node, Sinu-Atrial,Node, Sinuatrial,Node, Sinus,Nodes, Sino-Atrial,Nodes, Sinoatrial,Nodes, Sinu-Atrial,Nodes, Sinuatrial,Nodes, Sinus,Sino Atrial Node,Sino-Atrial Nodes,Sinoatrial Nodes,Sinu Atrial Node,Sinu-Atrial Nodes,Sinuatrial Nodes,Sinus Nodes
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D018345 Mice, Knockout Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes. Knockout Mice,Mice, Knock-out,Mouse, Knockout,Knock-out Mice,Knockout Mouse,Mice, Knock out
D020710 RGS Proteins A large family of evolutionarily conserved proteins that function as negative regulators of HETEROTRIMERIC GTP-BINDING PROTEINS. RGS PROTEINS act by increasing the GTPase activity of the G alpha subunit of a heterotrimeric GTP-binding protein, causing it to revert to its inactive (GDP-bound) form. Regulators of G-Protein Signaling Proteins,RGS Protein (G-Protein Signaling),Regulators of G Protein Signaling Proteins
D066298 In Vitro Techniques Methods to study reactions or processes taking place in an artificial environment outside the living organism. In Vitro Test,In Vitro Testing,In Vitro Tests,In Vitro as Topic,In Vitro,In Vitro Technique,In Vitro Testings,Technique, In Vitro,Techniques, In Vitro,Test, In Vitro,Testing, In Vitro,Testings, In Vitro,Tests, In Vitro,Vitro Testing, In

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