The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics

Zuberi, Zia; Birnbaumer, Lutz; Tinker, Andrew

doi:10.1152/ajpregu.90625.2008

Cited by 35 publications

(37 citation statements)

References 48 publications

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“…However, emerging data from the analysis of knock-out mice indicates that is some instances there may be little functional redundancy in vivo. For example, Gnai2 −/− mice have a selective defect of parasympathetic modulation of heart rate not seen in Gnai1/Gnai3 double knock-out mice 36. Furthermore, a recent reconstitution study in Sf9 cells that showed CXCL12 induced GTPase activity in cell membrane preparations containing either Gα i1 or Gα i2 exceeded that noted with membranes containing Gα i3 and greatly exceeded those expressing Gα o suggesting that CXCR4 preferentially couples to Gα i1 and Gα i2 37.…”

Section: Discussionmentioning

confidence: 99%

Variations in Gnai2 and Rgs1 expression affect chemokine receptor signaling and the organization of secondary lymphoid organs

et al. 2010

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Ligand bound chemoattractant receptors activate the heterotrimeric G protein Gi to stimulate downstream signaling pathways to properly position lymphocytes in lymphoid organs. Here we show how variations the expression of a chemokine receptor and in two components in the signaling pathway, Gαi2 and RGS1, affects the output fidelity of the signaling pathway. Examination of B cells from mice with varying numbers of intact alleles of Ccr7, Rgs1, Gnai2, and Gnai3 provided the basis for these results. Loss of a single allele of either Gnai2 or Rgs1 affected CCL19 triggered chemotaxis, while loss of a single allele of Ccr7, which encodes the cognate CCL19 receptor, had little effect. Emphasizing the importance of Gnai2, B cells lacking Gnai3 expression responded to chemokines better than did wild type B cells. At an organismal level, variations in Rgs1 and Gnai2 expression affected marginal zone B cell development, splenic architecture, lymphoid follicle size, and germinal center morphology. Gnai2 expression was also needed for the proper alignment of MOMA-1+ macrophages and MAdCAM-1+ endothelial cells along marginal zone sinuses in the spleen. These data indicate that chemoattractant receptors, heterotrimeric G-proteins, and RGS protein expression levels have a complex inter-relationship that affects the responses to chemoattractant exposure.

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Section: Discussionmentioning

confidence: 99%

Variations in Gnai2 and Rgs1 expression affect chemokine receptor signaling and the organization of secondary lymphoid organs

et al. 2010

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“…Details of telemetry system (TEA-F20, DSI, St Pauls) implantation have previously been described 20 . Recording leads were tunnelled subcutaneously in a conventional “Lead II” ECG configuration to continuously record surface ECG after a 2 week period of surgical recovery.…”

Section: Methodsmentioning

confidence: 99%

Absence of the Inhibitory G-Protein Gα _i2 Predisposes to Ventricular Cardiac Arrhythmia

Zuberi

Nobles²,

Dyson³

et al. 2010

Circ: Arrhythmia and Electrophysiology

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Background We have explored the role that inhibitory heterotrimeric G-proteins have in ventricular arrhythmia. Methods and Results We studied mice with global genetic deletion of Gαi2 (Gαi2 (−/−)) and find that they have a prolonged QT interval on the surface ECG when awake and studied with telemetry. We used in-vivo electrophysiology studies and found that the Gαi2 (−/−) mice have a reduced ventricular effective refractory period and a predisposition to ventricular tachycardia when challenged with programmed electrical stimulation. Neither control nor mice with combined global deletion of Gαi1 and Gαi3 showed these abnormalities. There was no evidence for structural heart disease at this time point in the Gαi2 (−/−) mice as assessed by cardiac histology and echocardiography. The absence of Gαi2 thus leads to a primary electrical abnormality and we explored the basis for this. Single isolated ventricular cells studied using patch clamping showed that Gαi2 (−/−) mice had a prolonged ventricular action potential duration but steeper action potential shortening as the diastolic interval was reduced in restitution studies. Gene expression studies showed increased expression of L-type Ca2+ channel subunits and patch clamping revealed an increase in these currents in Gαi2 (−/−) mice. There were no changes in K+ currents. Conclusion Thus the absence of inhibitory G-protein signaling in particular that mediated via Gαi2 is a substrate for ventricular arrhythmias.

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“…These studies suggested that GIRK1/4 activation by the m2R receptor is mediated by Gα i2 or Gα i3 (Fu et al, 2006;Sowell et al, 1997) but not via Gα o , despite the abundance of the latter (Luetje, Tietje, Christian, & Nathanson, 1988) and despite its specific participation in m2R coupling to voltage-dependent Ca 2+ channels in the heart (Valenzuela et al, 1997;Ye, Sowell, Vassilev, Milstone, & Mortensen, 1999). The selective role of Gα i2 but not Gα i1 or Gα o in the muscarinic activation of cardiac GIRK has been confirmed in Gα knockout mice (Zuberi, Birnbaumer, & Tinker, 2008). The exquisite selectivity observed in the heart cannot be easily reconstituted in heterologous systems, where all Gα i/o species can donate Gβγ to activate GIRKs.…”

Section: Specificity Of Gpcr-girk Signaling: Relative Roles Of Gα Andmentioning

confidence: 98%

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

Dascal

Kahanovitch

2015

International Review of Neurobiology

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The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics

Abstract: Zuberi Z, Birnbaumer L, Tinker A. The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics.

Cited by 35 publications

References 48 publications

Variations in Gnai2 and Rgs1 expression affect chemokine receptor signaling and the organization of secondary lymphoid organs

Variations in Gnai2 and Rgs1 expression affect chemokine receptor signaling and the organization of secondary lymphoid organs

Absence of the Inhibitory G-Protein Gα _i2 Predisposes to Ventricular Cardiac Arrhythmia

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

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The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics

Abstract: Zuberi Z, Birnbaumer L, Tinker A. The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics.

Cited by 35 publications

References 48 publications

Variations in Gnai2 and Rgs1 expression affect chemokine receptor signaling and the organization of secondary lymphoid organs

Variations in Gnai2 and Rgs1 expression affect chemokine receptor signaling and the organization of secondary lymphoid organs

Absence of the Inhibitory G-Protein Gα i2 Predisposes to Ventricular Cardiac Arrhythmia

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

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Absence of the Inhibitory G-Protein Gα _i2 Predisposes to Ventricular Cardiac Arrhythmia