Allosteric modulation of metabotropic glutamate receptors

Abstract

The development of receptor subtype-selective ligands by targeting allosteric sites of G protein-coupled receptors (GPCRs) has proven highly successful in recent years. One GPCR family that has greatly benefited from this approach is the metabotropic glutamate receptors (mGlus). These family C GPCRs participate in the neuromodulatory actions of glutamate throughout the CNS, where they play a number of key roles in regulating synaptic transmission and neuronal excitability. A large number of mGlu subtype-selective allosteric modulators have been identified, the majority of which are thought to bind within the transmembrane regions of the receptor. These modulators can either enhance or inhibit mGlu functional responses and, together with mGlu knockout mice, have furthered the establishment of the physiologic roles of many mGlu subtypes. Numerous pharmacological and receptor mutagenesis studies have been aimed at providing a greater mechanistic understanding of the interaction of mGlu allosteric modulators with the receptor, which have revealed evidence for common allosteric binding sites across multiple mGlu subtypes and the presence for multiple allosteric sites within a single mGlu subtype. Recent data have also revealed that mGlu allosteric modulators can display functional selectivity toward particular signal transduction cascades downstream of an individual mGlu subtype. Studies continue to validate the therapeutic utility of mGlu allosteric modulators as a potential therapeutic approach for a number of disorders including anxiety, schizophrenia, Parkinson's disease, and Fragile X syndrome.

FIGURE 1

Schematic representation of mGlus at the synapse. Group I mGlus, mGlu₁ and mGlu₅, are generally localized postsynaptically, while Group II mGlus (mGlu₂ and mGlu₃) and Group III mGlus (mGlu₄, mGlu₇, and mGlu₈) are localized in presynaptic locations, although exceptions occur. mGlu₆ is not shown in this figure as it is only found localized postsynaptically in the retina. On presynaptic terminals, Group II and III receptors often function to inhibit neurotransmitter release, whereas Group I mGlus promote release when present. Postsynaptically, Group I mGlus signal via G_q proteins to increase intracellular calcium, whereas Group II mGlus signal via G_i/o proteins to inhibit cAMP production. mGlu₅ activation also can potentiate N-methyl-D-aspartate (NMDA) glutamate receptor currents. In addition to the NMDA receptor, the other ionotropic glutamate receptors, the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and kainite receptors, respond to glutamate with increases in intracellular sodium or calcium, promoting cell excitability. In the CNS, mGlu₃ and mGlu₅ have also been found to be expressed on glia.

FIGURE 2

Representation of the mGlu structure. mGlus possess a large N-terminal extracellular domain that contains the orthosteric binding site of the endogenous ligand glutamate, referred to as the venus flytrap domain (VFD). The extracellular VFD is connected to seven transmembrane (7TM) domains via a cysteine-rich domain. Allosteric ligands bind to sites other than the orthosteric glutamate binding site, such as within the 7TM domain. Group I mGlus couple to G_q/11 proteins, whereas the Group II and Group III mGlus couple to G_i/o proteins.

FIGURE 3

Models of allosteric interactions. (A) Allosteric ternary complex model (ACTM), (B) Operational model of allosterism. In these models, the affinity (equilibrium dissociation constant) of the orthosteric ligand (A) for the receptor (R) is defined as K_A, while the affinity of the allosteric modulator (B) is K_B. α is the affinity cooperativity parameter, denoting the direction and magnitude of the allosteric interaction. The pharmacological effect or stimulus arising from the orthosteric agonist occupied receptor is S_A, whereas that arising from the modulator occupied receptor is S_B. β is the efficacy cooperativity parameter, describing the change in S_A when both orthosteric and allosteric sites are occupied. τ_A denotes the coupling efficiency of the orthosteric ligand, E_m represents the maximal system response, while n is the slope factor that links occupancy to response.