Opel, A;
(2013)
The role of regulators of G-protein signalling (RGS) in the predisposition to atrial fibrillation.
Doctoral thesis , UCL (University College London).
Abstract
The electrophysiological basis of atrial fibrillation (AF) is unknown. Regulators of G-protein signalling (RGS) act to deactivate G-protein signalling; they interact with the α subunit and accelerate intrinsic GTP-ase activity. RGS 4 negatively regulates inhibitory Gαi/o and Gαq/11 signalling. Absence of RGS 4 may increase G-protein gated inwardly rectifying potassium (GIRK) currents, shorten the atrial effective refractory period and promote atrial arrhythmia. The absence of RGS 4 results in continued Gαq/11 and thus calcium (Ca2+) signalling which may predispose to atrial arrhythmia. Does attenuation of RGS 4 promote AF? What is the mechanism? In vivo studies were performed in global RGS 4 knockout (-/-) and wild type (+/+) mice. Electrophysiological studies (EPS) were performed and ECG and EP parameters recorded. AF induction was attempted. Telemetry probes were inserted and conscious mouse ECGs were studied for AF and atrial ectopics (AE). Heart rate variability (HRV) was measured. Atrial cardiomyocytes were studied with patch-clamping and confocal microscopy. ECG and EP parameters were comparable. RGS 4 (-/-) developed AF. Conscious RGS 4 (-/-) were tachycardic, and had an enhanced bradycardic response to carbachol (CCh). ECG and HRV parameters of RGS 4 (+/+) and RGS 4 (-/-) without and with CCh were comparable. CCh-treated RGS 4 (-/-) had disrupted HRV, pauses and AE compared to RGS 4 (-/-) alone, but no AF. At patching, GIRK was not implicated but single cell restitution curves showed a steeper slope in RGS 4 (-/-). There was an increase in frequency of Ca2+ sparks in RGS 4 (-/-) compared to RGS 4 (+/+) in the absence and presence of endothelin-1 (ET-1). 2-aminoethoxydiphenyl borate (2-APB) abolished sparks. Sparks were reduced in amplitude in RGS 4 (-/-) in the absence of ET-1, but were longer in duration, time to peak and tau. A subset analysis showed that the left atrium had a greater frequency of Ca2+ sparks than the right atrium, and that these were comparatively longer in duration, time to peak and tau. RGS 4 (-/-) mice are predisposed to AF. There is good evidence that this is mediated via Gαq/11-IP3-Ca2+. RGS 4 is a potential therapeutic target in the treatment of AF. More recently RGS 6 has been found to be expressed in the heart and negatively regulates inhibitory Gαi/o signalling. EPS with AF induction were performed in RGS 6 (-/-) and RGS 6 (+/+) mice, with greater inducibility in RGS 6 (-/-) mice. It is possible that RGS 6 mediates its effects via Gαi-GIRK and could be a therapeutic target in the treatment of AF but further mechanistic studies are underway.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | The role of regulators of G-protein signalling (RGS) in the predisposition to atrial fibrillation |
| Language: | English |
| Additional information: | Permission for digitisation not received. |
| Keywords: | Atrial fibrillation, Regulators of G-protein signalling, RGS 4, RGS 6, Calcium |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1394270 |
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