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• W3174266150 abstract "Myenteric interstitial cells of Cajal (ICC-MY) in the mouse small intestine are pacemaker cells that generate and propagate electrical slow waves. Conduction of slow waves to smooth muscle cells activates voltage-gated Ca2+ channels and coordinates rhythmic contractions of intestinal muscles. Slow waves are activated by intracellular Ca2+ release events firing asynchronously from multiple release sites within ICC-MY to activate the Cl− channel Ano1, the resulting depolarization of which forms slow waves. 1 Propagation of slow waves through the ICC-MY network depends upon activation of a voltage dependent, T-type Ca2+ conductance (Cav3.2). Previous studies have suggested that mitochondria play an important role in the Ca2+ signaling responsible for slow waves, and slow waves in mouse small intestine, guinea-pig stomach and canine colon were blocked by pharmacological agents that inhibit the electron transport chain, reduce mitochondrial transmembrane potential and prevent mitochondrial Ca2+ uptake (FCCP, CCCP and Antimycin). 2 We used in-situ Ca2+ imaging from the small intestines of mice expressing a genetically encoded Ca2+ indicator (GCaMP3) exclusively in ICC (GCaMP3 activated using Cre-LoxP approach, driven off the Kit promoter) to visualize Ca2+ transients in ICC-MY and used spatio-temporal particle-based analysis techniques to quantify the effects of mitochondrial inhibitors on Ca2+ transients in ICC-MY. The protonophores FCCP (1 μM, n=6) and CCCP (1 μM, n=6), the ETC inhibitor, Antimycin (10 μM, n=5), and the mitochondrial Na+/Ca2+ exchanger inhibitor CGP-37157 (30 μM, n=6) either abolished or drastically reduced Ca2+ transients in ICC-MY. This effect was not due to ATP depletion, since oligomycin (1 μM, n=6) had no effect on Ca2+ transients. We also used the patch-clamp technique to measure Ano1 and T-type Ca2+ (Cav3.2) currents in HEK 293 cells to examine the effects of these drugs on key membrane conductances that are essential for slow wave propagation in ICC-MY. Antimycin (1–10 μM, n=5) blocked Ano1 and reduced Cav3.2 currents (n=4). CCCP (1–3 μM, n=5) had no effect on Ano1 but significantly reduced Cav3.2 currents (n=5). Both Ano1 and Cav3.2 currents were inhibited by CGP-37157 (10–30 μM, n=5). Thus, the inhibitory effects of mitochondrial drugs on ICC-MY Ca2+ signalling and slow wave generation can be explained by direct antagonism of the conductances that generate and propagate slow waves and their effects are not necessarily due to mitochondrial effects. Our findings suggest that ICC pacemaker models, which emphasize a role for mitochondrial Ca2+ handling based on similar pharmacological evidence, should be interpreted with caution. Support or Funding Information Supported by P01 DK 41315 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal." @default.
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• W3174266150 date "2018-04-01" @default.
• W3174266150 modified "2023-09-27" @default.
• W3174266150 title "The effect of mitochondrial inhibitors on Ca 2+ signalling and pacemaking conductances in interstitial cells of Cajal in the mouse small intestine" @default.
• W3174266150 cites W2005855950 @default.
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• W3174266150 doi "https://doi.org/10.1096/fasebj.2018.32.1_supplement.764.3" @default.
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