The effects of mitochondrial inhibitors on Ca2+ signalling and electrical conductances required for pacemaking in interstitial cells of Cajal in the mouse small intestine.

Cell Calcium
Bernard T DrummKenton M Sanders

Abstract

Interstitial cells of Cajal (ICC-MY) are pacemakers that generate and propagate electrical slow waves in gastrointestinal (GI) muscles. Slow waves appear to be generated by the release of Ca2+ from intracellular stores and activation of Ca2+-activated Cl- channels (Ano1). Conduction of slow waves to smooth muscle cells coordinates rhythmic contractions. Mitochondrial Ca2+ handling is currently thought to be critical for ICC pacemaking. Protonophores, inhibitors of the electron transport chain (FCCP, CCCP or antimycin) or mitochondrial Na+/Ca2+ exchange blockers inhibited slow waves in several GI muscles. Here we utilized Ca2+ imaging of ICC in small intestinal muscles in situ to determine the effects of mitochondrial drugs on Ca2+ transients in ICC. Muscles were obtained from mice expressing a genetically encoded Ca2+ indicator (GCaMP3) in ICC. FCCP, CCCP, antimycin, a uniporter blocker, Ru360, and a mitochondrial Na+/Ca2+ exchange inhibitor, CGP-37157 inhibited Ca2+ transients in ICC-MY. Effects were not due to depletion of ATP, as oligomycin did not affect Ca2+ transients. Patch-clamp experiments were performed to test the effects of the mitochondrial drugs on key pacemaker conductances, Ano1 and T-type Ca2+ (CaV3.2), in HEK2...Continue Reading

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Citations

Jun 17, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Bernard T DrummKenton M Sanders
Aug 7, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Anthony C JohnsonBeverley Greenwood-Van Meerveld
May 2, 2020·The Journal of Physiological Sciences : JPS·Mohammed M IslamSatoshi Matsuoka
May 28, 2019·The Journal of Physiology·Bernard T DrummKenton M Sanders
Dec 8, 2019·The Journal of Physiology·Bernard T DrummKenton M Sanders
Apr 8, 2020·Frontiers in Physiology·Haifeng ZhengKenton M Sanders

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