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

Gerasimenko, Julia ORCID:, Charlesworth, Richard M., Sherwood, Mark W., Ferdek, Pawel E., Mikoshiba, Katsuhiko, Parrington, John, Petersen, Ole H. ORCID: and Gerasimenko, Oleg V. ORCID: 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: 06 May 2023 00:48

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