Quantitative Analysis Reveals Multiple Mechanisms of Allosteric Modulation of the mGlu5 Receptor in Rat Astroglia

Positive and negative allosteric modulators (PAMs and NAMs, respectively) of the type 5 metabotropic glutamate (mGlu5) receptor have demonstrable therapeutic potential in an array of neurological and psychiatric disorders. Here, we have used rat cortical astrocytes to investigate how PAMs and NAMs mediate their activity and reveal marked differences between PAMs with respect to their modulation of orthosteric agonist affinity and efficacy. Affinity cooperativity factors () were assessed using [3H]2-methyl-6-(phenylethynyl)-pyridine (MPEP)-PAM competi-tion binding in the absence and presence of orthosteric agonist, whereas efficacy cooperativity factors () were calculated from net affinity/efficacy cooperativity parameters () obtained from analyses of the abilities of PAMs to potentiate [3H]inositol phosphate accumulation in astrocytes stimulated with a sub