title: Substance P induces inward current and regulates pacemaker currents through tachykinin NK1 receptor in cultured interstitial cells of Cajal of murine small intestine.
abstract: We investigated whether substance P modulates pacemaker currents generated in cultured interstitial cells of Cajal of murine small intestine using whole cell patch-clamp techniques at 30 degrees C. Interstitial cells of Cajal generated spontaneous inward currents (pacemaker currents) at a holding potential of -70 mV. Tetrodotoxin, nifedipine, tetraethylammonium, 4-aminopyridine, or glibenclamide did not change the frequency and amplitude of pacemaker currents. However, divalent cations (Ni2+, Mn2+, Cd2+, and Co2+), nonselective cationic channel blockers (gadolinium and flufenamic acid), and a reduction of external Na+ from normal to 1 mM inhibited pacemaker currents indicating that nonselective cation channels are involved in their generation. Substance P depolarized the membrane potential in current clamp mode and produced tonic inward pacemaker currents with reduced frequency and amplitude in voltage clamp mode. [D-Arg1, D-Trp7,9, Leu11] substance P, a tachykinin NK1 receptor antagonist, blocked these substance P-induced responses. Furthermore, [Sar9, Met(O2)11] substance P, a specific tachykinin NK1 receptor agonist, depolarized the membrane and tonic inward currents mimicked those of substance P. Substance P continued to produce tonic inward currents in external Ca2+-free solution or in the presence of chelerythrine, a protein kinase C inhibitor. However, substance P-induced tonic inward currents were blocked by thapsigargin, a Ca2+-ATPase inhibitor in the endoplasmic reticulum or by an external 1 mM Na+ solution. Our results demonstrate that substance P may modulate intestinal motility by acting on the interstitial cells of Cajal by activating nonselective cation channels via the release of intracellular Ca2+ induced by tachykinin NK1 receptor stimulation.
authors.affiliation: Department of Physiology, College of Medicine, Chosun University, 375 Seosuk-dong, Gwanju, Republic of Korea.
authors.forename: Jae Yeoul
authors.initials: JY
authors.lastname: Jun
authors.forename: Seok
authors.initials: S
authors.lastname: Choi
authors.forename: Cheol Ho
authors.initials: CH
authors.lastname: Yeum
authors.forename: In Youb
authors.initials: IY
authors.lastname: Chang
authors.forename: Ho Jin
authors.initials: HJ
authors.lastname: You
authors.forename: Chan Kuk
authors.initials: CK
authors.lastname: Park
authors.forename: Man Yoo
authors.initials: MY
authors.lastname: Kim
authors.forename: In Deok
authors.initials: ID
authors.lastname: Kong
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Kim
authors.forename: Kyu Pil
authors.initials: KP
authors.lastname: Lee
authors.forename: Insuk
authors.initials: I
authors.lastname: So
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Kim
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent / Q000494:pharmacology; D002478:Cells, Cultured; D004594:Electrophysiology / Q000379:methods; D017615:Enteric Nervous System / Q000187:drug effects / Q000502:physiology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects / Q000294:innervation* / Q000473:pathology*; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000294:innervation; D064729:Neurokinin-1 Receptor Antagonists; D009543:Nifedipine / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D012849:Sinoatrial Node / Q000187:drug effects / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D015320:Tachykinins / Q000494:pharmacology / Q000502:physiology; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D053119:Benzophenanthridines; D002413:Cations, Divalent; D007473:Ion Channels; D064729:Neurokinin-1 Receptor Antagonists; D010617:Phenanthridines; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; D013373:Substance P; D013779:Tetrodotoxin; D019789:Tetraethylammonium; D012964:Sodium; D015761:4-Aminopyridine; C016299:chelerythrine; D009543:Nifedipine; D005905:Glyburide; D002118:Calcium