Eun-Mi Hur^1,2, Yong-Soo Park^1,2, Yang Hoon Huh^3,4, Seung Hyun Yoo^3,4, Kyung-Chul Woo^1,2, Bo-Hwa Choi^1,2, and Kyong-Tai Kim<sup>1,2

1</sup> National Research Laboratory of Molecular Neurophysiology, Pohang University of Science and Technology, Hyo-ja dong, San31, Pohang, 790-784, South Korea
² Department of Life Science, Pohang University of Science and Technology, Hyo-ja dong, San31, Pohang, 790-784, South Korea
³ National Creative Research Initiative Center for Secretory Granule Research, Inha University College of Medicine, Jung Gu, Incheon 400-712, South Korea
⁴ Department of Biochemistry, Inha University College of Medicine, Jung Gu, Incheon 400-712, South Korea

Correspondence to Kyong-Tai Kim

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.