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Both RyRs and TPCs are required for NAADP-induced intracellular Ca2+ release

Gerasimenko, Julia, Charlesworth, Richard M., Sherwood, Mark W., Ferdek, Pawel E., Mikoshiba, Katsuhiko, Parrington, John, Petersen, Ole H. and Gerasimenko, Oleg V. 2015. Both RyRs and TPCs are required for NAADP-induced intracellular Ca2+ release. Cell Calcium 58 (3) , pp. 237-245. 10.1016/j.ceca.2015.05.005

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Intracellular Ca2+ release is mostly mediated by inositol trisphosphate, but intracellular cyclic-ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are important messengers in many systems. Whereas cADPR generally activates type 2 ryanodine receptors (RyR2s), the NAADP-activated Ca2+ release mechanism is less clear. Using knockouts and antibodies against RyRs and Two-Pore Channels (TPCs), we have compared their relative importance for NAADP-induced Ca2+ release from two-photon permeabilized pancreatic acinar cells. In these cells, cholecystokinin-elicited Ca2+ release is mediated by NAADP. TPC2-KO reduced NAADP-induced Ca2+ release by 64%, but the combination of TPC2-KO and an antibody against TPC1, significantly reduced Ca2+ release by 86% (64% vs. 86%, p < 0.0002). In RyR3-KO, NAADP-evoked Ca2+ release reduced by ∼50% but, when combined with antibodies against RyR1, responses were 90% inhibited. Antibodies against RyR2 had practically no effect on NAADP-evoked Ca2+ release, but reduced release in response to cADPR by 55%. Antibodies to RyR1 inhibited NAADP-induced Ca2+ liberation by 81%, but only reduced cADPR responses by 30%. We conclude that full NAADP-mediated Ca2+ release requires both TPCs and RyRs. The sequence of relative importance for NAADP-elicited Ca2+ release from the all stores is RyR1 > TPC2 > RyR3 > TPC1 >> RyR2. However, when assessing NAADP-induced Ca2+ release solely from the acidic stores (granules/endosomes/lysosomes), antibodies against TPC2 and TPC1 virtually abolished the Ca2+ liberation as did antibodies against RyR1 and RyR3. Our results indicate that the primary, but very small, NAADP-elicited Ca2+ release via TPCs from endosomes/lysosomes triggers the detectable Ca2+-induced Ca2+ release via RyR1 and RyR3 occurring from the granules and the ER.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology
Uncontrolled Keywords: Pancreatic acinar cells; TPC2 knockouts; cADPR; Acidic store; RyR3 knockouts
Additional Information: This is an open access article under the terms of the CC-BY Attribution 4.0 International license
Publisher: Elsevier
ISSN: 0143-4160
Funders: MRC
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 17 May 2015
Last Modified: 15 Feb 2022 09:42

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