Protein kinase C mediates spontaneous tone in the cat lower esophageal sphincter

Craig Hillemeier, Khalil N. Bitar, Uydong Sohn, Piero Biancani

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The intracellular pathways responsible for maintenance of tone in the lower esophageal sphincter (LES) are not well understood. We show that the protein kinase C (PKC) antagonists (1-(5-isoquinolinesulphonyl)-2- methylpiperazine dihydrochloride) and calphostin C reduce spontaneous resting tone in LES muscle strips, whereas the calmodulin antagonist N-(6-aminohexyl- 5-chloro-1-naphthalenesulfonamide hydrochloride) has no effect, which suggests that LES tone is maintained by a PKC-mediated mechanism. In addition, U73122, an inhibitor of phosphatidylinositol-4,5-bisphosphate (PIP2)-specific phosphotipase C, and D609, an inhibitor of phosphatidycholine-specific phospholipase C, reduced diacylglycerol formation and LES tone in a concentration-dependent manner. Finally, diacylglycerol levels and PKC activity were reduced during relaxation of the LES induced by the inhibitory neurotransmitter vasoactive intestinal peptide. These data suggest that resting LES tone is associated with elevated diacylglycerol levels and PKC activity, which are reduced during relaxation. Diacylglycerol is derived from at least two different sources. Hydrolysis of PIP2 by PIP2- specific phospholipase C produces equimolar amounts of inositol 1,4,5- triphosphate and diacylglycerol, which may interact synergistically to activate PKC and develop tone. Furthermore, PKC-mediated contraction may be augmented by additional diacylglycerol production arising from the hydrolysis of phosphatidylcholine by phosphatidylcholine-specific phospholipase C.

Original languageEnglish (US)
Pages (from-to)144-149
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume277
Issue number1
StatePublished - Apr 1 1996

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Lower Esophageal Sphincter
Protein Kinase C
Cats
Diglycerides
Diacylglycerol Kinase
Type C Phospholipases
Hydrolysis
Inositol 1,4,5-Trisphosphate
Vasoactive Intestinal Peptide
Calmodulin
Phosphatidylinositols
Phosphatidylcholines
Neurotransmitter Agents
Maintenance
Muscles

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Hillemeier, Craig ; Bitar, Khalil N. ; Sohn, Uydong ; Biancani, Piero. / Protein kinase C mediates spontaneous tone in the cat lower esophageal sphincter. In: Journal of Pharmacology and Experimental Therapeutics. 1996 ; Vol. 277, No. 1. pp. 144-149.
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Hillemeier, C, Bitar, KN, Sohn, U & Biancani, P 1996, 'Protein kinase C mediates spontaneous tone in the cat lower esophageal sphincter', Journal of Pharmacology and Experimental Therapeutics, vol. 277, no. 1, pp. 144-149.

Protein kinase C mediates spontaneous tone in the cat lower esophageal sphincter. / Hillemeier, Craig; Bitar, Khalil N.; Sohn, Uydong; Biancani, Piero.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 277, No. 1, 01.04.1996, p. 144-149.

Research output: Contribution to journalArticle

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N2 - The intracellular pathways responsible for maintenance of tone in the lower esophageal sphincter (LES) are not well understood. We show that the protein kinase C (PKC) antagonists (1-(5-isoquinolinesulphonyl)-2- methylpiperazine dihydrochloride) and calphostin C reduce spontaneous resting tone in LES muscle strips, whereas the calmodulin antagonist N-(6-aminohexyl- 5-chloro-1-naphthalenesulfonamide hydrochloride) has no effect, which suggests that LES tone is maintained by a PKC-mediated mechanism. In addition, U73122, an inhibitor of phosphatidylinositol-4,5-bisphosphate (PIP2)-specific phosphotipase C, and D609, an inhibitor of phosphatidycholine-specific phospholipase C, reduced diacylglycerol formation and LES tone in a concentration-dependent manner. Finally, diacylglycerol levels and PKC activity were reduced during relaxation of the LES induced by the inhibitory neurotransmitter vasoactive intestinal peptide. These data suggest that resting LES tone is associated with elevated diacylglycerol levels and PKC activity, which are reduced during relaxation. Diacylglycerol is derived from at least two different sources. Hydrolysis of PIP2 by PIP2- specific phospholipase C produces equimolar amounts of inositol 1,4,5- triphosphate and diacylglycerol, which may interact synergistically to activate PKC and develop tone. Furthermore, PKC-mediated contraction may be augmented by additional diacylglycerol production arising from the hydrolysis of phosphatidylcholine by phosphatidylcholine-specific phospholipase C.

AB - The intracellular pathways responsible for maintenance of tone in the lower esophageal sphincter (LES) are not well understood. We show that the protein kinase C (PKC) antagonists (1-(5-isoquinolinesulphonyl)-2- methylpiperazine dihydrochloride) and calphostin C reduce spontaneous resting tone in LES muscle strips, whereas the calmodulin antagonist N-(6-aminohexyl- 5-chloro-1-naphthalenesulfonamide hydrochloride) has no effect, which suggests that LES tone is maintained by a PKC-mediated mechanism. In addition, U73122, an inhibitor of phosphatidylinositol-4,5-bisphosphate (PIP2)-specific phosphotipase C, and D609, an inhibitor of phosphatidycholine-specific phospholipase C, reduced diacylglycerol formation and LES tone in a concentration-dependent manner. Finally, diacylglycerol levels and PKC activity were reduced during relaxation of the LES induced by the inhibitory neurotransmitter vasoactive intestinal peptide. These data suggest that resting LES tone is associated with elevated diacylglycerol levels and PKC activity, which are reduced during relaxation. Diacylglycerol is derived from at least two different sources. Hydrolysis of PIP2 by PIP2- specific phospholipase C produces equimolar amounts of inositol 1,4,5- triphosphate and diacylglycerol, which may interact synergistically to activate PKC and develop tone. Furthermore, PKC-mediated contraction may be augmented by additional diacylglycerol production arising from the hydrolysis of phosphatidylcholine by phosphatidylcholine-specific phospholipase C.

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