C. Hillemeier et al., PROTEIN-KINASE-C MEDIATES SPONTANEOUS TONE IN THE CAT LOWER ESOPHAGEAL SPHINCTER, The Journal of pharmacology and experimental therapeutics, 277(1), 1996, pp. 144-149
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 n
o 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 phospholipase C, and D609, an inhibit
or of phosphatidycholine-specific phospholipase C, reduced diacylglyce
rol formation and LES tone in a concentration-dependent manner. Finall
y, diacylglycerol levels and PKC activity were reduced during relaxati
on of the LES induced by the inhibitory neurotransmitter vasoactive in
testinal peptide. These data suggest that resting LES tone is associat
ed with elevated diacylglycerol levels and PKC activity, which are red
uced during relaxation. Diacylglycerol is derived from at least two di
fferent sources. Hydrolysis of PIP2 by PIP2-specific phospholipase C p
roduces equimolar amounts of inositol 1,4,5-triphosphate and diacylgly
cerol, which may interact synergistically to activate PKC and develop
tone. Furthermore, PKC-mediated contraction may be augmented by additi
onal diacylglycerol production arising from the hydrolysis of phosphat
idylcholine by phosphatidylcholine-specific phospholipase C.