Figure 2.

Connection between store-operated Ca²⁺ entry (SOCE) and PKA. SOCE, and its principal mediators STIM1 and Orai1, play increasingly important roles in the migration of a number of cell types. During SOCE, signals generated by receptors (e.g. G-protein coupled receptors (GPCR) or receptor tyrosine kinases (RTK)) at the plasma membrane activate phospholipases C (PLC) to generate IP₃, which causes the release of Ca^2+- from intracellular stores via the IP₃R. Store depletion activates STIM1, which re-localizes within the ER membrane to allow interaction with and activation of the plasma membrane Ca²⁺ channel Orai1. Store-depletion has also been shown to stimulate adenylyl cyclase (AC) and activate PKA. Reciprocally, PKA may regulate the SOCE pathway at a number of levels, e.g. through phosphorylation and modulation of many PLC-coupled receptors, the IP₃R, phospholamban associated with the sarco-/endoplasmic reticulum Ca²⁺-ATPase (SERCA), and possibly Orai1 itself (see Figure 3).