Figure 3.

Noncanonical Ca²⁺ channels. (1) G-protein-coupled receptors activated by endothelin-1 (ET-1) or angiotensin-II (Ang-II), produce InsP₃ that activates Ca²⁺ release via InsP₃ receptors (IP₃RII), which cross talks with RyR2 to modify Ca²⁺-induced Ca²⁺ release (CICR). (2) Ca²⁺ release from InsP₃R2 present at the perinuclear SR and the nuclear envelope stimulates nuclear Ca²⁺ signaling pathways. (3) β-Adrenergic receptor (β-AR) activation leads to the activation of protein kinase A (PKA), which in turn enhances the activity of the CD38 enzyme. (4) CD38 produces nicotinic acid adenine dinucleotide phosphate (NAADP) that promotes Ca²⁺ leak via endolysosomal two-pore channels (TPCs). (5) Activation of CD38 also generates cyclic ADP-ribose (cADPR), which acts on the RyR2 to enhance its activity. (6) To refill the SR as well as affect cytosolic Ca²⁺ levels, the STIM/ORAI/TRP system may be engaged.