Allosteric modulation of metabotropic glutamate receptors

Abstract

Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu4 belongs to a subfamily of mGlus that is coupled to Gi/o G proteins, and represents a promising target for the treatment of Parkinson’s disease. Allosteric modulators of mGlu4 provide several advantages over the orthosteric ligands in terms of drug discovery. However, the complicated pharmacology of allosteric modulators remain largely unexplored. The ubiquitous autacoid and neuromodulator, histamine, biases the signaling of small molecule positive allosteric modulators of mGlu4 toward calcium-dependent pathways via concomitant activation of histamine H1 receptor. These results suggest that allosteric modulators may exhibit functional selective effects in the presence of signaling convergence. In addition, mGlu2 and mGlu4 form a hetero-complex in native brain tissues, and differentially regulate the efficacies of allosteric modulators in cell lines and at the corticostriatal synapse. These data greatly extend our current understanding of mGlu receptor interaction and function and shed light on the development of allosteric modulators for tissue-specific therapy.