Substance P induces inward current and regulates pacemaker currents through tachykinin NK 1 receptor in cultured interstitial cells of Cajal of murine small intestine

Jae Yeoul Jun, Seok Choi, Cheol Ho Yeum, In Youb Chang, Ho Jin You, Chan Kuk Park, Man Yoo Kim, In Deok Kong, Min Ji Kim, Kyu Pil Lee, Insuk So, Ki Whan Kim

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36 Scopus citations

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°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 (Ni 2+ , Mn 2+ , Cd 2+ , and Co 2+ ), 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-Arg 1 , D-Trp 7,9 , Leu 11 ] substance P, a tachykinin NK 1 receptor antagonist, blocked these substance P-induced responses. Furthermore, [Sar 9 , Met(O 2 ) 11 ] substance P, a specific tachykinin NK 1 receptor agonist, depolarized the membrane and tonic inward currents mimicked those of substance P. Substance P continued to produce tonic inward currents in external Ca 2+ -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 Ca 2+ -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 Ca 2+ induced by tachykinin NK 1 receptor stimulation.

Original languageEnglish
Pages (from-to)35-42
Number of pages8
JournalEuropean Journal of Pharmacology
Volume495
Issue number1
DOIs
StatePublished - 8 Jul 2004

Keywords

  • Interstitial cell of Cajal
  • Neurokinin receptor1
  • Pacemaker current
  • Small intestine
  • Substance P

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