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Departments of Physiology and Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298 - 0711
This study examined the expression of
inositol 1,4,5-trisphosphate (IP3) receptor
(IP3R) types and PKG isoforms in isolated gastric smooth
muscle cells and determined the ability of PKG and PKA to phosphorylate
IP3Rs and inhibit IP3-dependent
Ca2+ release, which mediates the initial phase of
agonist-induced contraction. PKG-I
and PKG-I
were expressed in
gastric smooth muscle cells, together with IP3-R-associated
cG-kinase substrate, a protein that couples PKG-I to
IP3R-I. IP3R-I and IP3R-III were also expressed, but only IP3R-I was phosphorylated by PKA
and PKG in vitro and exclusively by PKG in vivo. Sequential
phosphorylation by PKA and by PKG-I in vitro showed that PKA
phosphorylated the same site as PKG (presumably S1755) and
an additional PKA-specific site (S1589). In intact muscle
cells, agents that activated PKG or both PKG and PKA induced
IP3R-I phosphorylation that was reversed by the PKG
inhibitor
(8R,9S,11s)-(
)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,1H,-2,7b,11a-trizadizo-benzo9(a,g)cycloocta(c,d,e)-trinden-1-one. Agents that activated PKA induced IP3R-I phosphorylation in
permeabilized but not intact muscle cells, implying that PKA does not
gain access to IP3R-I in intact muscle cells. The pattern
of IP3R-I phosphorylation in vivo and in vitro was more
consistent with phosphorylation by PKG-I. Phosphorylation of
IP3R-I in microsomes by PKG, PKA, or a combination of PKG
and PKA inhibited IP3-induced Ca2+ release to
the same extent, implying that inhibition was mediated by
phosphorylation of the PKG-specific site. We conclude that IP3R-I is selectively phosphorylated by PKG-I in intact
smooth muscle resulting in inhibition of IP3-dependent
Ca2+ release.
relaxation, gastric muscle, calcium release
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