P. Thams et al., EXOGENOUS ARACHIDONIC-ACID INACTIVATES PROTEIN-KINASE-C IN MOUSE PANCREATIC-ISLETS, Acta Physiologica Scandinavica, 149(2), 1993, pp. 227-235
The effect of arachidonic acid on protein kinase C activity and insuli
n secretion in mouse islets was investigated. Arachidonic acid stimula
ted protein kinase C activity in islet cytosol and membrane fractions
by substituting for phosphatidylserine. Stimulation by arachidonic aci
d was dependent on either Ca2+ or the phorbol ester 12-O-tetradecanoyl
phorbol 13-acetate, was potentiated by the combined addition of Ca2+ 12-O-tetradecanoylphorbol 13-acetate, and did not further increase pr
otein kinase C activity in the presence of saturating concentrations o
f phosphatidylserine. Arachidonic acid stimulation of protein kinase C
was prevented by binding of arachidonic acid to albumin. In the absen
ce of extracellular Ca2+, exogenous arachidonic acid stimulated insuli
n secretion. Arachidonic acid-induced insulin secretion was not potent
iated by 12-O-tetradecanoylphorbol 13-acetate and was not prevented by
the protein kinase C inhibitor staurosporine, suggesting that arachid
onic acid-induced insulin secretion may occur independently of protein
kinase C activation. Arachidonic acid-induced insulin secretion in Ca
2+-free medium was on the other hand potentiated by addition of extrac
ellular Ca2+. Stimulation of insulin secretion by exogenous arachidoni
c acid was associated with inactivation of protein kinase C. Inactivat
ion of protein kinase C was also observed in islet homogenate after pr
e-incubation with arachidonic acid. Arachidonic acid-induced protein k
inase C inactivation in islet homogenate was prevented by albumin or M
gATP. Inactivation by arachidonic acid in intact islets was, however,
not produced during enzyme isolation and was not prevented by inclusio
n of albumin or MgATP during preparation of protein kinase C extracts.
In conclusion, it is suggested, that arachidonic acid, by inactivating
protein kinase C, may exert toxic effects in islets, and that arachid
onic acid may stimulate insulin secretion by a non-physiological mecha
nism, possibly involving an ionophoretic effect of arachidonic acid to
induce Ca2+-mediated insulin release.