Coupling of AMPA receptors with the Na(+)/Ca(2+) exchanger in cultured rat astrocytes.
Astrocytes exhibit three transmembrane Ca(2+) influx pathways: voltage-gated Ca(2+) channels (VGCCs), the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) class of glutamate receptors, and Na(+)/Ca(2+) exchangers. Each of these pathways is thought to be capable of mediating a significant increase in Ca(2+) concentration ([Ca(2+)](i)); however, the relative importance of each and their interdependence in the regulation astrocyte [Ca(2+)](i) is not known. We demonstrate here that 100 microM AMPA in the presence of 100 microM cyclothiazide (CTZ) causes an increase in [Ca(2+)](i) in cultured cerebral astrocytes that requires transmembrane Ca(2+) influx. This increase of [Ca(2+)](i) is blocked by 100 microM benzamil or 0.5 microM U-73122, which inhibit reverse-mode operation of the Na(+)/Ca(2+) exchanger by independent mechanisms. This response does not require Ca(2+) influx through VGCCs, nor does it depend upon a significant Ca(2+) influx through AMPA receptors (AMPARs). Additionally, AMPA in the presence of CTZ causes a depletion of thapsigargin-sensitive intracellular Ca(2+) stores, although depletion of these Ca(2+) stores does not decrease the peak [Ca(2+)](i) response to AMPA. We propose that activation of AMPARs in astrocytes can cause [Ca(2+)](i) to increase through the reverse mode operation of the Na(+)/Ca(2+) exchanger with an associated release of Ca(2+) from intracellular stores. This proposed mechanism requires neither Ca(2+)-permeant AMPARs nor the activation of VGCCs to be effective.
Smith
J P
JP
Department of Neurosciences, University of New Mexico, School of Medicine, Albuquerque, NM 87131, USA.
Cunningham
L A
LA
Partridge
L D
LD
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001581:Benzothiadiazines / Q000494:pharmacology; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D001581:Benzothiadiazines; D018690:Excitatory Amino Acid Agonists; D012333:RNA, Messenger; D018091:Receptors, AMPA; D019831:Sodium-Calcium Exchanger; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C004639:cyclothiazide; D002118:Calcium