Dataset Information

DREADD technology reveals major impact of Gq signalling on cardiac electrophysiology.

ABSTRACT: AIMS:Signalling via Gq-coupled receptors is of profound importance in many cardiac diseases such as hypertrophy and arrhythmia. Nevertheless, owing to their widespread expression and the inability to selectively stimulate such receptors in vivo, their relevance for cardiac function is not well understood. We here use DREADD technology to understand the role of Gq-coupled signalling in vivo in cardiac function. METHODS AND RESULTS:We generated a novel transgenic mouse line that expresses a Gq-coupled DREADD (Dq) in striated muscle under the control of the muscle creatine kinase promotor. In vivo injection of the DREADD agonist clozapine-N-oxide (CNO) resulted in a dose-dependent, rapid mortality of the animals. In vivo electrocardiogram data revealed severe cardiac arrhythmias including lack of P waves, atrioventricular block, and ventricular tachycardia. Following Dq activation, electrophysiological malfunction of the heart could be recapitulated in the isolated heart ex vivo. Individual ventricular and atrial myocytes displayed a positive inotropic response and arrhythmogenic events in the absence of altered action potentials. Ventricular tissue sections revealed a strong co-localization of Dq with the principal cardiac connexin CX43. Western blot analysis with phosphor-specific antibodies revealed strong phosphorylation of a PKC-dependent CX43 phosphorylation site following CNO application in vivo. CONCLUSION:Activation of Gq-coupled signalling has a major impact on impulse generation, impulse propagation, and coordinated impulse delivery in the heart. Thus, Gq-coupled signalling does not only modulate the myocytes' Ca2+ handling but also directly alters the heart's electrophysiological properties such as intercellular communication. This study greatly advances our understanding of the plethora of modulatory influences of Gq signalling on the heart in vivo.

SUBMITTER: Kaiser E

PROVIDER: S-EPMC6736079 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

DREADD technology reveals major impact of Gq signalling on cardiac electrophysiology.

Kaiser Elisabeth E Tian Qinghai Q Wagner Michael M Barth Monika M Xian Wenying W Schröder Laura L Ruppenthal Sandra S Kaestner Lars L Boehm Ulrich U Wartenberg Philipp P Lu Huiyan H McMillin Sara M SM Bone Derek B J DBJ Wess Jürgen J Lipp Peter P

Cardiovascular research 20190501 6

<h4>Aims</h4>Signalling via Gq-coupled receptors is of profound importance in many cardiac diseases such as hypertrophy and arrhythmia. Nevertheless, owing to their widespread expression and the inability to selectively stimulate such receptors in vivo, their relevance for cardiac function is not well understood. We here use DREADD technology to understand the role of Gq-coupled signalling in vivo in cardiac function.<h4>Methods and results</h4>We generated a novel transgenic mouse line that exp ...[more]

PMID: 30321287

Similar Datasets

Project description:BackgroundGlial cells of the central nervous system directly influence neuronal activity by releasing neuroactive small molecules, including glutamate. Long-lasting cocaine-induced reductions in extracellular glutamate in the nucleus accumbens core (NAcore) affect synaptic plasticity responsible for relapse vulnerability.MethodsWe transduced NAcore astrocytes with an adeno-associated virus vector expressing hM3D designer receptor exclusively activated by a designer drug (DREADD) under control of the glial fibrillary acidic protein promoter in 62 male Sprague Dawley rats, 4 dominant-negative soluble N-ethylmaleimide-sensitive factor attachment protein receptor mice, and 4 wild-type littermates. Using glutamate biosensors, we measured NAcore glutamate levels following intracranial or systemic administration of clozapine N-oxide (CNO) and tested the ability of systemic CNO to inhibit reinstated cocaine or sucrose seeking following self-administration and extinction training.ResultsAdministration of CNO in glial fibrillary acidic protein-hM3D-DREADD transfected animals increased NAcore extracellular glutamate levels in vivo. The glial origin of released glutamate was validated by an absence of CNO-mediated release in mice expressing a dominant-negative soluble N-ethylmaleimide-sensitive factor attachment protein receptor variant in glia. Also, CNO-mediated release was relatively insensitive to N-type calcium channel blockade. Systemic administration of CNO inhibited cue-induced reinstatement of cocaine seeking in rats extinguished from cocaine but not sucrose self-administration. The capacity to inhibit reinstated cocaine seeking was prevented by systemic administration of the group II metabotropic glutamate receptor antagonist LY341495.ConclusionsDREADD-mediated glutamate gliotransmission inhibited cue-induced reinstatement of cocaine seeking by stimulating release-regulating group II metabotropic glutamate receptor autoreceptors to inhibit cue-induced synaptic glutamate spillover.

Project description:BackgroundCardiac electrophysiology training of young cardiologists forms the foundation of optimal heart rhythm patient care. In particular, cardiac electrophysiology is characterized by continuous innovation and has progressed rapidly over the last few years. This may have led to a gap between clinical training and the new technologies and could significantly change training requirements.ObjectiveThe aim of the survey was to obtain the opinion of young cardiologists about the current importance and satisfaction of cardiac electrophysiology training and to identify areas for improvement.MethodsThe survey was conducted in May 2020. Young DGK (Deutschen Gesellschaft für Kardiologie, German Society for Cardiology) members were contacted via e‑mail and asked to answer an online-based questionnaire. The questionnaire containing information about the current status, satisfaction, and structures of educational and clinical proficiency of cardiac electrophysiology in Germany.ResultsOverall, 131 young DGK members completed the survey. Mean age was 33 ± 3.3 years and 68% of the participants were male. Among the participants, 64% were cardiology fellows, while 36% were qualified. A total of 72 participants (53%) reported overall satisfaction with their clinical training and 50% of the participants held the opinion that cardiac electrophysiology should become a larger part of their education. Training courses and fellowships were rated mostly positive (70% vs. 93%, respectively); however, the later were unknown to 41% of the participants. Areas identified for improvement included the following: establishment of general cardiac electrophysiology rotation; enabling access to procedures to gain invasive skills; increased advertising for training courses and fellowships; increase of online-based training courses.ConclusionThe survey underlines the interest of young cardiologists in an intensified cardiac electrophysiology training within their cardiology training.

Dataset Information

DREADD technology reveals major impact of Gq signalling on cardiac electrophysiology.

Publications

DREADD technology reveals major impact of Gq signalling on cardiac electrophysiology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets