Ca. Leech et al., VOLTAGE-INDEPENDENT CALCIUM CHANNELS MEDIATE SLOW OSCILLATIONS OF CYTOSOLIC CALCIUM THAT ARE GLUCOSE-DEPENDENT IN PANCREATIC BETA-CELLS, Endocrinology, 135(1), 1994, pp. 365-372
Pancreatic beta-cells and HIT-T15 cells exhibit oscillations of cytoso
lic calcium ([Ca2+](i)) that are dependent on glucose metabolism and a
ppear to trigger pulsatile insulin secretion. Significantly, differenc
es in the pattern of this [Ca2+](i) oscillatory activity may have impo
rtant implications for our understanding of how glucose homeostasis is
achieved during the feeding and fasting states. When single beta-cell
s are exposed to a stepwise increase in glucose concentration that mim
ics the transition from fasting to feeding states, fast irregular osci
llations of [Ca2+](i) are observed. Alternatively, when single beta-ce
lls are equilibrated in a steady state concentration of glucose that m
imics the fasting state, slow periodic oscillations of [Ca2+](i) are n
oted. Here we report a fundamental difference in the mechanism by whic
h glucose induces these two types of [Ca2+](i) oscillatory activity. I
n agreement with previous studies, we substantiate a role for L-type v
oltage-dependent Ca2+ channels as mediators of the fast oscillations o
f [Ca2+](i) observed after a stepwise increase in glucose concentratio
n. In marked contrast, we report that voltage-independent calcium chan
nels (VICCs) mediate slow oscillations of [Ca2+](i) that occur when be
ta-cells are equilibrated in steady state concentrations of glucose. S
low [Ca2+](i) oscillations are mediated by VICCs which are pharmacolog
ically and biophysically distinguishable from voltage-dependent Ca2+ c
hannels that mediate fast oscillations. Specifically, slow [Ca2+](i) o
scillations are blocked by extracellular La3+, but not by nifedipine,
and are independent of changes in membrane potential. Measurements of
membrane conductance also indicate an important role for VICCs, as dem
onstrated by a steady state inward Ca2+ current that is blocked by La3
+. The steady state Ca2+ current appears to generate slow [Ca2+](i) os
cillations by triggering Ca2+-induced Ca2+ release from intracellular
Ca2+ stores, a process that is mimicked by extracellular application o
f caffeine, a sensitizer of the ryanodine receptor/Ca2+ release channe
l. Depletion of intracellular Ca2+ stores with thapsigargin stimulated
Mn2+ influx, suggesting the presence of Ca2+-release-activated Ca2+ c
hannels. Taken together, these observations are consistent with a role
for VICCs (possibly G-type channels) and/or Ca2+-release-activated Ca
2+ channels as mediators of slow [Ca2+](i) oscillations in beta-cells.
We propose that slow oscillations of [Ca2+](i) probably serve as impo
rtant initiators of insulin secretion under conditions in which tight
control of glucose homeostasis is necessary, as is the case during the
fasting normoglycemic state.