Figure 2.

Mechanisms of InsP₃-mediated regulation of ECC in atrial and ventricular cardiomyocytes. Atria: GPCRs activated by ET-1 or Ang II produce InsP₃ that stimulates Ca²⁺ release via InsP₃ receptors type 1 or 2 (InsP₃R1/2). This InsP₃ mediated Ca²⁺ release in turn acts either via priming of proximal RyRs for Ca²⁺ release or via activation of Ca²⁺-sensitive adenylyl cyclases (AC1 or AC8) and activation of PKA by cAMP, which then phosphorylates RyRs, modulates Ca²⁺ transients and hence strength of contraction. Ventricle: Ca²⁺ release via InsP₃Rs facilitates RyR opening and enhances their recruitment during ECC (1). However, the enhanced activity of RyRs leads also to enhanced SR Ca²⁺ leak (2), which reduces the Ca²⁺ load in the SR and can lead to activation of NCX. If the SR Ca²⁺ leak is of sufficient amplitude, via NCX, it can trigger substantial Na⁺ influx into the cell leading to membrane depolarization manifest as a delayed after-depolarisation (DAD) and potentially AP generation (3). AC, adenylyl cyclase; Ang II, angiotensin II; ATP, adenosine-5′-triphosphate; cAMP, cyclic adenosine monophosphate, Ca_v1.2, α1C, subunit of voltage-gated L-type calcium channel; DAD, delayed after-depolarizations; ET-1, endothelin 1; GPCR, G protein-coupled receptor; IP₃, inositol 1,4,5-trisphosphate; IP₃R1/2, inositol trisphosphate receptor type 1/2; NCX, sodium-calcium exchanger; PKA, protein kinase A; RyR2, ryanodine receptor type 2; SERCA, sarco-endoplasmic reticulum Ca²⁺-ATPase; SR, sarcoplasmic reticulum. (Online version in colour.)