Received for publication June 1, 2005.
Revised August 23, 2005.
Accepted for publication August 30, 2005.

Allosteric potentiators of metabotropic glutamate receptor subtype 5 have differential effects on different signaling pathways in cortical astrocytes

Abstract

The metabotropic glutamate receptor subtype 5 (mGluR5) activates calcium mobilization and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation in cortical astrocytes. These are independent signaling systems and can be differentially regulated. We recently discovered two novel selective allosteric potentiators of mGluR5, 3,3'-difluorobenzaldazine (DFB) and N-{4-chloro-2-[(1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) methyl]phenyl}-2-hydroxybenzamide (CPPHA). In studies of mGluR5 activation of calcium transients in recombinant systems, both DFB and CPPHA are without effect on baseline calcium levels but induce parallel leftward shifts in the concentration response curve to agonists. However, it is conceivable that these compounds will have differential effects on different signaling pathways in native systems. Here, we examined the effects of CPPHA and DFB on mGluR5-induced calcium transients and ERK1/2 phosphorylation in cultured rat cortical astrocytes. Both potentiators induced parallel leftward shifts of the concentration response curves of DHPG- and glutamate-induced calcium transients in astrocytes. These effects are identical to their effects on mGluR5 expressed in HEK293 or CHO cells. DFB induced a similar shift of concentration-response curve of DHPG-induced ERK1/2 phosphorylation. Interestingly, CPPHA induced an increase in basal mGluR5-mediated ERK1/2 phosphorylation and potentiated the effect of low concentrations of agonists. In contrast, CPPHA significantly decreased ERK1/2 phosphorylation induced by high concentrations of agonists. Thus, CPPHA has qualitatively different effects on mGluR5-mediated calcium responses and ERK1/2 phosphorylation. Taken together, these data provide evidence that different allosteric potentiators can differentially modulate coupling of a single receptor to different signaling pathways.

Key words: G protein coupled receptors, allosteric potentiators, astrocytes, calcium transients, extracellular signal regulated kinase, metabotropic glutamate receptors

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