The Effects of Mitochondrial Inhibitors on Ca Signalling and Electrical Conductances Required for Pacemaking in Interstitial Cells of Cajal in the Mouse Small Intestine

Overview

Journal Cell Calcium

Publisher Elsevier

Specialties Cell Biology
Endocrinology

Date 2018 May 12

PMID 29748128

Citations 13

Authors

Bernard T Drumm

Tae S Sung

Haifeng Zheng

Salah A Baker

Sang D Koh

Kenton M Sanders

Affiliations

Soon will be listed here.

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 Ca from intracellular stores and activation of Ca-activated Cl channels (Ano1). Conduction of slow waves to smooth muscle cells coordinates rhythmic contractions. Mitochondrial Ca handling is currently thought to be critical for ICC pacemaking. Protonophores, inhibitors of the electron transport chain (FCCP, CCCP or antimycin) or mitochondrial Na/Ca exchange blockers inhibited slow waves in several GI muscles. Here we utilized Ca imaging of ICC in small intestinal muscles in situ to determine the effects of mitochondrial drugs on Ca transients in ICC. Muscles were obtained from mice expressing a genetically encoded Ca indicator (GCaMP3) in ICC. FCCP, CCCP, antimycin, a uniporter blocker, Ru360, and a mitochondrial Na/Ca exchange inhibitor, CGP-37157 inhibited Ca transients in ICC-MY. Effects were not due to depletion of ATP, as oligomycin did not affect Ca transients. Patch-clamp experiments were performed to test the effects of the mitochondrial drugs on key pacemaker conductances, Ano1 and T-type Ca (Ca3.2), in HEK293 cells. Antimycin blocked Ano1 and reduced Ca3.2 currents. CCCP blocked Ca3.2 current but did not affect Ano1 current. Ano1 and Cav3.2 currents were inhibited by CGP-37157. Inhibitory effects of mitochondrial drugs on slow waves and Ca signalling in ICC can be explained by direct antagonism of key pacemaker conductances in ICC that generate and propagate slow waves. A direct obligatory role for mitochondria in pacemaker activity is therefore questionable.

Citing Articles

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