Interaction of ATP sensor, cAMP sensor, Ca2+ sensor, and voltage-dependent Ca2+ channel in insulin granule exocytosis.
ATP, cAMP, and Ca(2+) are the major signals in the regulation of insulin granule exocytosis in pancreatic beta cells. The sensors and regulators of these signals have been characterized individually. The ATP-sensitive K(+) channel, acting as the ATP sensor, couples cell metabolism to membrane potential. cAMP-GEFII, acting as a cAMP ... sensor, mediates cAMP-dependent, protein kinase A-independent exocytosis, which requires interaction with both Piccolo as a Ca(2+) sensor and Rim2 as a Rab3 effector. l-type voltage-dependent Ca(2+) channels (VDCCs) regulate Ca(2+) influx. In the present study, we demonstrate interactions of these molecules. Sulfonylurea receptor 1, a subunit of ATP-sensitive K(+) channels, interacts specifically with cAMP-GEFII through nucleotide-binding fold 1, and the interaction is decreased by a high concentration of cAMP. Localization of cAMP-GEFII overlaps with that of Rim2 in plasma membrane of insulin-secreting MIN6 cells. Localization of Rab3 co-incides with that of Rim2. Rim2 mutant lacking the Rab3 binding region, when overexpressed in MIN6 cells, is localized exclusively in cytoplasm, and impairs cAMP-dependent exocytosis in MIN6 cells. In addition, Rim2 and Piccolo bind directly to the alpha(1)1.2-subunit of VDCC. These results indicate that ATP sensor, cAMP sensor, Ca(2+) sensor, and VDCC interact with each other, which further suggests that ATP, cAMP, and Ca(2+) signals in insulin granule exocytosis are integrated in a specialized domain of pancreatic beta cells to facilitate stimulus-secretion coupling.
Mesh Terms:
Adenosine Triphosphate, Animals, Binding Sites, COS Cells, Calcium, Calcium Channels, Carrier Proteins, Cell Membrane, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cytoplasmic Granules, Cytoskeletal Proteins, Exocytosis, GTP-Binding Proteins, Glutathione Transferase, Guanine Nucleotide Exchange Factors, Humans, Insulin, Insulinoma, Membrane Potentials, Mice, Nerve Tissue Proteins, Neuropeptides, P-Glycoprotein, Pancreatic Neoplasms, Potassium Channels, Potassium Channels, Inwardly Rectifying, Rats, Recombinant Fusion Proteins, Signal Transduction, Tumor Cells, Cultured
Adenosine Triphosphate, Animals, Binding Sites, COS Cells, Calcium, Calcium Channels, Carrier Proteins, Cell Membrane, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cytoplasmic Granules, Cytoskeletal Proteins, Exocytosis, GTP-Binding Proteins, Glutathione Transferase, Guanine Nucleotide Exchange Factors, Humans, Insulin, Insulinoma, Membrane Potentials, Mice, Nerve Tissue Proteins, Neuropeptides, P-Glycoprotein, Pancreatic Neoplasms, Potassium Channels, Potassium Channels, Inwardly Rectifying, Rats, Recombinant Fusion Proteins, Signal Transduction, Tumor Cells, Cultured
J. Biol. Chem.
Date: Feb. 27, 2004
PubMed ID: 14660679
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