J. Biol. Chem., Vol. 259, Issue 20, 12350-12356, Oct, 1984
Effect of intracellular Ca2+ on insulin-like growth factor II. internalization into pancreatic acini. Roles of insulin and cholecystokinin
J Mossner, CD Logsdon, N Potau, JA Williams and ID Goldfine
Previously, we reported that pancreatic acini have specific receptors for
the insulin-like growth factors (IGF) I and II. We now report that the
binding of 125I-labeled IGF II to mouse pancreatic acini is maximally
increased by 100 nM insulin (51%) and is maximally reduced by 10 nM
cholecystokinin octapeptide (CCK8) (34%), but is not affected by other
regulatory peptides such as somatostatin or glucagon. Since many
polypeptide hormones are internalized, we determined whether this
regulation of IGF II binding occurred via a change in internalization. Acid
washing or trypsinization has been shown to remove surface-bound hormone
while the acid- or trypsin-resistant radioactivity represents internalized
radioligand. Insulin increased and CCK8 decreased the internalization of
IGF II as determined by these techniques. Studies of IGF II binding to
acini at low temperature (15 degrees C) and binding to particulate
fractions from acini were also consistent with the effect of insulin to
increase and CCK8 to decrease the internalization of IGF II. When insulin
and CCK8 were added together, the inhibitory effect of CCK8 predominated,
indicating that CCK8 acted distal to the effect of insulin. Several lines
of evidence suggest that this effect of CCK8 was via the CCK receptor and
was mediated via a change in intracellular Ca2+: the effect of CCK8 on
inhibiting IGF II binding was blocked by the cholecystokinin antagonist
N2,O2'-dibutyryl cGMP; the cholinergic agent carbachol (1-100 microM),
which acts through the muscarinic receptor to increase intracellular Ca2+,
also inhibited IGF II binding; the Ca2+ ionophore A23187 (1-5 microM)
mimicked the effects of CCK8 and carbachol. These data indicate, therefore,
that CCK8 and possibly insulin may regulate the internalization of IGF II
via intracellular Ca2+. Moreover, the data raise the possibility that
alterations of hormone internalization may be a general phenomenon of
hormone-hormone interaction.
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