Coupling of AMPA receptors with the Na(+)/Ca(2+) exchanger in cultured rat astrocytes

Brain Res. 2000 Dec 22;887(1):98-109. doi: 10.1016/s0006-8993(00)02973-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Benzothiadiazines / pharmacology
  • COS Cells
  • Calcium / metabolism*
  • Cells, Cultured
  • Cerebral Cortex
  • Excitatory Amino Acid Agonists / pharmacology
  • Hippocampus
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / drug effects
  • Receptors, AMPA / metabolism*
  • Sodium-Calcium Exchanger / drug effects
  • Sodium-Calcium Exchanger / metabolism*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology


  • Benzothiadiazines
  • Excitatory Amino Acid Agonists
  • RNA, Messenger
  • Receptors, AMPA
  • Sodium-Calcium Exchanger
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • cyclothiazide
  • Calcium