title: Propagation of slow waves requires IP3 receptors and mitochondrial Ca2+ uptake in canine colonic muscles.
abstract: In the gastrointestinal (GI) tract electrical slow waves yield oscillations in membrane potential that periodically increase the open probability of voltage-dependent Ca2+ channels and facilitate phasic contractions. Slow waves are generated by the interstitial cells of Cajal (ICC), and these events actively propagate through ICC networks within the walls of GI organs. The mechanism that entrains spontaneously active pacemaker sites throughout ICC networks to produce regenerative propagation of slow waves is unresolved. Agents that block inositol 1,4,5-trisphosphate (IP3) receptors and mitochondrial Ca2+ uptake were tested on the generation of slow waves in the canine colon. A partitioned chamber apparatus was used to test the effects of blocking slow-wave generation on propagation. We found that active propagation occurred along strips of colonic muscle, but when the pacemaker mechanism was blocked in a portion of the tissue, slow waves decayed exponentially from the point where the pacemaker mechanism was inhibited. An IP3 receptor inhibitor, mitochondrial inhibitors, low external Ca2+, and divalent cations (Mn2+ and Ni2+) caused exponential decay of the slow waves in regions of muscle exposed to these agents. These data demonstrate that the mechanism that initiates slow waves is reactivated from cell-to-cell during the propagation of slow waves. Voltage-dependent conductances present in smooth muscle cells are incapable of slow-wave regeneration. The data predict that partial loss of or disruptions to ICC networks observed in human motility disorders could lead to incomplete penetration of slow waves through GI organs and, thus, to defects in myogenic regulation.
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno 89557, USA. sean@physio.unr.edu
authors.forename: Sean M
authors.initials: SM
authors.lastname: Ward
authors.forename: Salah A
authors.initials: SA
authors.lastname: Baker
authors.forename: Andrew
authors.initials: A
authors.lastname: de Faoite
authors.forename: Kenton M
authors.initials: KM
authors.lastname: Sanders
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000493:pharmacokinetics*; D015220:Calcium Channels / Q000502:physiology*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D003106:Colon / Q000502:physiology*; D004285:Dogs; D005260:Female; D005769:Gastrointestinal Motility / Q000502:physiology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008297:Male; D008345:Manganese / Q000494:pharmacology; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000502:physiology*; D009532:Nickel / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D001896:Boron Compounds; D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D008345:Manganese; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000968:Antimycin A; D009532:Nickel; C109986:2-aminoethoxydiphenyl borate; D002118:Calcium