Astrocytes exhibit three transmembrane Ca2+ influx pathways: voltage-gated
Ca2+ channels (VGCCs), the alpha -amino-3-hydroxy-5-methyl-4-isoxazole prop
ionic acid (AMPA) class of glutamate receptors, and Na+/Ca2+ exchangers. Ea
ch of these pathways is thought to be capable of mediating a significant in
crease in Ca2+ concentration ([Ca2+](i)); however, the relative importance
of each and their interdependence in the regulation astrocyte [Ca2+](i) is
not known. We demonstrate here that 100 muM AMPA in the presence of 100 muM
cyclothiazide (CTZ) causes an increase in [Ca2+](i) in cultured cerebral a
strocytes that requires transmembrane Ca2+ influx. This increase of [Ca2+](
i) is blocked by 100 muM benzamil or 0.5 muM U-73122, which inhibit reverse
-mode operation of the Na+/Ca2+ exchanger by independent mechanisms. This r
esponse does not require Ca2+ influx through VGCCs, nor does it depend upon
a significant Ca2+ influx through AMPA receptors (AMPARs). Additionally, A
MPA in the presence of CTZ causes a depletion of thapsigargin-sensitive int
racellular Ca2+ stores, although depletion of these Ca2+ stores does not de
crease the peak [Ca2+](i) response to AMPA. We propose that activation of A
MPARs in astrocytes can cause [Ca2+](i) to increase through the reverse mod
e operation of the Na+/Ca2+ exchanger with an associated release of Ca2+ fr
om intracellular stores. This proposed mechanism requires neither Ca2+-perm
eant AMPARs nor the activation of VGCCs to be effective. (C) 2000 Elsevier
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