Fig. 11

Schematic diagram illustrating the mechanism through which TRPC7 positively regulates the automaticity of cardiomyocytes. G protein-coupled receptors (GPCRs) locating on the plasma membrane (PM) sense the external ligands such as hormones, neurotransmitters, and growth factors, transduce the signal to activate phospholipase C (PLC) which hydrolyzes the phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol trisphosphate (IP₃) and diacylglycerol (DAG). TRPC7 is then directly activated by DAG, mediating the Ca²⁺ influx. Ca²⁺ permeated through TRPC7 may activate the forward mode of the Na⁺-Ca²⁺ exchanger (NCX), leading Na⁺ influx and depolarization. This depolarization would then accelerate diastolic depolarization (DD) and increase AP firing rate. On the other hand, Ca²⁺ permeated through TRPC7 may also increase the activity of ryanodine receptor 2 (RyR2) locating on the SR, probably through CaMKII and phosphorylation of RyR2, leading to an increase of the localized calcium releases (LCRs). These LCRs are then coupled to inward NCX current, and subsequently accelerate the DD and AP firing rate. At the same time, CaMKII may also increase the phosphorylation of PLN, which subsequently increases the activity of SERCA. The enhancement of the activity of both RyR2 and SERCA result in the acceleration of CaTs