Abstract
Ca(2+) is a highly versatile intracellular signal that regulates many different cellular processes, and cells have developed mechanisms to have exquisite control over Ca(2+) signaling. Epidermal growth factor (EGF), which fails to mobilize intracellular Ca(2+) when administrated alone, becomes capable of evoking [Ca(2+)](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 (IP(3)R1), cAMP-dependent protein kinase (PKA), EGF receptor (EGFR), and an A-kinase anchoring protein, yotiao. The IP(3)R complex functions as a focal point to promote Ca(2+) release in two ways: (1) it facilitates PKA-dependent phosphorylation of IP(3)R1 in response to BK-induced elevation of cAMP, and (2) it couples the plasmalemmal EGFR with IP(3)R1 at the Ca(2+) store located juxtaposed to the plasma membrane. Our study illustrates how the junctional membrane IP(3)R complex connects different signaling pathways to define the fidelity and specificity of Ca(2+) signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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A Kinase Anchor Proteins
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Bradykinin / metabolism
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Bradykinin / pharmacology
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Calcium / metabolism*
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Calcium Channels / metabolism*
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Calcium Signaling / drug effects
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Calcium Signaling / physiology*
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Cell Membrane / metabolism*
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cytoskeletal Proteins / metabolism
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Epidermal Growth Factor / metabolism*
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Epidermal Growth Factor / pharmacology
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ErbB Receptors
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Exocytosis / drug effects
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Exocytosis / physiology
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Glycoproteins / drug effects
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Glycoproteins / metabolism
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Inositol 1,4,5-Trisphosphate Receptors
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Intercellular Junctions / metabolism*
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Membrane Glycoproteins / metabolism*
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PC12 Cells
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Phosphorylation / drug effects
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Rats
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Up-Regulation / drug effects
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Up-Regulation / physiology
Substances
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A Kinase Anchor Proteins
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Adaptor Proteins, Signal Transducing
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Akap9 protein, rat
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Calcium Channels
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Cytoskeletal Proteins
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Glycoproteins
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Inositol 1,4,5-Trisphosphate Receptors
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Itpr1 protein, rat
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Membrane Glycoproteins
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Receptors, Cytoplasmic and Nuclear
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Epidermal Growth Factor
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Cyclic AMP
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Egfr protein, rat
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ErbB Receptors
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Cyclic AMP-Dependent Protein Kinases
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Bradykinin
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Calcium