Allosteric modulators of group III metabotropic glutamate receptors as novel therapeutics

METABOTROPIC GLUTAMATE RECEPTORS IN GLUTAMATERGIC NEUROTRANSMISSION

Glutamate is the major and most abundant excitatory neurotransmitter in the central nervous system (CNS). Due to its presence in most species, this amino acid represents one of the oldest neurotransmitters in nature. The regulation and activity of glutamate in the synapse is orchestrated by no less than three families of ionotropic receptors, three groups of metabotropic receptors, and five transporters (1). The existence of multiple subtypes and splice variants within each of these families and groups further adds to the complexity of this system. Contributing to the intricacy of glutamatergic regulation is the presence of allosteric sites for modulators in addition to the orthosteric glutamate binding site. The discovery of allosteric binding sites within the seven transmembrane (7TM) domains of the metabotropic glutamate receptors (mGluRs)

represents a novel mechanism for fine-tuning the effects of glutamate and provides insight into the generation of therapeutics with novel modes of action.