Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Endolysosomal Two-pore Channels Modulate Membrane Excitability and Stimulus-Secretion Coupling in Mouse Pancreatic β Cells

• Published in: The Journal of biological chemistry Vol. 290; no. 35; pp. 21376 - 21392
• Main Authors: Arredouani, Abdelilah, Ruas, Margarida, Collins, Stephan C., Parkesh, Raman, Clough, Frederick, Pillinger, Toby, Coltart, George, Rietdorf, Katja, Royle, Andrew, Johnson, Paul, Braun, Matthias, Zhang, Quan, Sones, William, Shimomura, Kenju, Morgan, Anthony J., Lewis, Alexander M., Chuang, Kai-Ting, Tunn, Ruth, Gadea, Joaquin, Teboul, Lydia, Heister, Paula M., Tynan, Patricia W., Bellomo, Elisa A., Rutter, Guy A., Rorsman, Patrik, Churchill, Grant C., Parrington, John, Galione, Antony
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28-08-2015; American Society for Biochemistry and Molecular Biology
• Subjects: Analytical chemistry; Animals; Calcium - metabolism; Calcium Channels - genetics; Calcium Channels - metabolism; Cell Biology; Cells, Cultured; Chemical Sciences; diabetes; endosome; Endosomes - metabolism; Glucose - metabolism; insulin; Insulin - metabolism; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; lysosome; Male; Membrane Potentials; Mice; Mice, Knockout; NADP - analogs & derivatives; NADP - metabolism; nicotinic acid adenine dinucleotide phosphate (NAADP); Organic chemistry; TPC1; TPC2; endosome; insulin; nicotinic acid adenine dinucleotide phosphate (NAADP); TPC2; diabetes; lysosome; TPC1; knockout; cultured; glucose/metabolism; calcium channels/genetics/ metabolism; insulin-secreting cells/cytology/ metabolism; mice; membrane potentials; cells; calcium/metabolism; endosomes/ metabolism; NADP/ analogs & derivatives/metabolism; animals; insulin/metabolism; male
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.671248

Pancreatic β cells are electrically excitable and respond to elevated glucose concentrations with bursts of Ca2+ action potentials due to the activation of voltage-dependent Ca2+ channels (VDCCs), which leads to the exocytosis of insulin granules. We have examined the possible role of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca2+ release from intracellular stores during stimulus-secretion coupling in primary mouse pancreatic β cells. NAADP-regulated Ca2+ release channels, likely two-pore channels (TPCs), have recently been shown to be a major mechanism for mobilizing Ca2+ from the endolysosomal system, resulting in localized Ca2+ signals. We show here that NAADP-mediated Ca2+ release from endolysosomal Ca2+ stores activates inward membrane currents and depolarizes the β cell to the threshold for VDCC activation and thereby contributes to glucose-evoked depolarization of the membrane potential during stimulus-response coupling. Selective pharmacological inhibition of NAADP-evoked Ca2+ release or genetic ablation of endolysosomal TPC1 or TPC2 channels attenuates glucose- and sulfonylurea-induced membrane currents, depolarization, cytoplasmic Ca2+ signals, and insulin secretion. Our findings implicate NAADP-evoked Ca2+ release from acidic Ca2+ storage organelles in stimulus-secretion coupling in β cells.
Background: TPCs are regulated by NAADP and other factors.
Results: NAADP-induced Ca2+ release from acidic stores evokes depolarizing currents in pancreatic β cells. Inhibition of NAADP signaling or TPC knock out attenuates Ca2+ signaling and insulin secretion.
Conclusion: NAADP-evoked Ca2+ release enhances β cell excitability and insulin secretion in response to glucose or sulfonylureas.
Significance: NAADP signaling pathways offer novel therapeutic targets for diabetes treatment.