Junctional membrane inositol 1,4,5-trisphosphate receptor complex coordinates sensitization of the silent EGF-induced Ca²⁺ signaling

Ca²⁺ is a highly versatile intracellular signal that regulates many different cellular processes, and cells have developed mechanisms to have exquisite control over Ca²⁺ signaling. Epidermal growth factor (EGF), which fails to mobilize intracellular Ca²⁺ when administrated alone, becomes capable of evoking [Ca²⁺]_i increase and exocytosis after bradykinin (BK) stimulation in chromaffin cells. Here, we provide evidence that this sensitization process is coordinated by a macromolecular signaling complex comprised of inositol 1,4,5-trisphosphate receptor type I (IP₃R1), cAMP-dependent protein kinase (PKA), EGF receptor (EGFR), and an A-kinase anchoring protein, yotiao. The IP₃R complex functions as a focal point to promote Ca²⁺ release in two ways: (1) it facilitates PKA-dependent phosphorylation of IP₃R1 in response to BK-induced elevation of cAMP, and (2) it couples the plasmalemmal EGFR with IP₃R1 at the Ca²⁺ store located juxtaposed to the plasma membrane. Our study illustrates how the junctional membrane IP₃R complex connects different signaling pathways to define the fidelity and specificity of Ca²⁺ signaling.