Ca2+ signals:
Molecular Mechanisms and Integrative Functions Collaborative Research Center 894

Project A19 - Peter Lipp

The role of Gq-dependent signaling for pacemaking, impulse propagation and contractility of the heart

Many processes in the heart are modulated via G protein-coupled receptors (GPCRs). While the role of Gi-, Go- and Gs-proteins for pacemaking, impulse propagation and the myocardial function are well understood, the contribution of Gq-protein coupled signaling to pacemaking and excitation conduction remains largely elusive. Because natural agonists and receptors often evoke multiple signaling pathways simultaneously, dissection of the contribution of Gq-protein coupled signaling has been difficult.

We will use inducible tissue-specific expression of a design receptor exclusively activated by design drugs (DREADD) for Gq-proteins to gain detailed insight into Gq-mediated signal transduction in the heart. In combination with tissue-specific expression of a genetically encoded Ca2+ sensor we will investigate Gq-dependent signaling on the submicroscopic level using ultra-fast confocal imaging and integrative functions on various levels, e.g. tissue (intact SA node imaging), intact organ (working heart) and organism (echocardiography and telemetry). Such an integrative approach will specifically address the contribution of Gq-mediated signaling to

(i) cardiac pacemaking,

(ii) impulse propagation and

(iii) modulation of contractility and excitability in the working myocardium under physiological conditions but also during cardiac hypertrophy and cardiac arrhythmia.