Substance P induces inward current and regulates pacemaker currents through tachykinin NK1 receptor in cultured interstitial cells of Cajal of murine small intestine.
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.
Jun
Jae Yeoul
JY
Department of Physiology, College of Medicine, Chosun University, 375 Seosuk-dong, Gwanju, Republic of Korea.
Choi
Seok
S
Yeum
Cheol Ho
CH
Chang
In Youb
IY
You
Ho Jin
HJ
Park
Chan Kuk
CK
Kim
Man Yoo
MY
Kong
In Deok
ID
Kim
Min Ji
MJ
Lee
Kyu Pil
KP
So
Insuk
I
Kim
Ki Whan
KW
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
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