Characterization of an Intracellular Alkaline Shift in Rat Astrocytes Triggered by Metabotropic Glutamate Receptors

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Abstract
Amos, Brian J. and Mitchell Chesler. Characterization of an intracellular alkaline shift in rat astrocytes triggered by metabotropic glutamate receptors. J. Neurophysiol. 79: 695–703, 1998. The modulation of intracellular pH by activation of metabotropic glutamate receptors was investigated in cultured and acutely dissociated rat astrocytes. One minute superfusion of 100 μM (1S,3R)-1-aminocyclopentane-1,3-dicarboxcylic acid (ACPD) evoked an alkaline shift of 0.13 ± 0.013 (mean ± SE) and 0.16 ± 0.03 pH units in cultured (cortical or cerebellar) and acutely dissociated cortical astrocytes, respectively. Alkalinizations were elicited by concentrations of ACPD as low as 1 μM. The ACPD response was mimicked by S-3-hydroxyphenylglycine (3-HPG) and by (s)-4-carboxy-3-hydroxyphenylglycine (4C-3HPG) but was not blocked by α-methyl-4-carboxyphenylglycine (MCPG) or (RS)-1-aminoindan-1,5-dicarboxcylic acid (AIDA), features consistent with an mGluR5 receptor–mediated mechanism. The ACPD-evoked alkaline shift was insensitive to amiloride, 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), and the v-type ATPase inhibitors 7-chloro-4-nitrobenz-2-oxa-1,3-diazol (NBD-Cl), bafilomycin, and concanamycin. The alkaline response persisted in Na+- or Cl−-free saline, but was reversibly blocked in bicarbonate-free, N-2-hydroxyethylpiperazine- N′-2-ethanesulfonic acid (HEPES)-buffered solutions. A bicarbonate-dependent and Na+-independent alkaline shift could also be elicited by either 3 mM caffeine or 1 μM ionomycin. These data suggest that a rise in cytosolic Ca2+activity is instrumental in triggering the alkalinizing mechanism and that this response is independent of the classic depolarization-induced alkalinization mediated by electrogenic sodium-bicarbonate cotransport.