Metabotropic Receptors

Metabotropic glutamate receptors (mGluRs) are seven transmembrane domain G-protein-coupled receptors that are activated by glutamate and that regulate neuronal excitability by a multiplicity of postsynaptic and presynaptic mechanisms. Eight distinct mGluRs have been identified by molecular cloning, some of which exist in multiple alternatively spliced forms. The family of mGluRs can be divided into two major groups based on the second-messenger systems to which they are coupled: those that increase phosphatidylinositol (PI) hydrolysis through activation of phospholipase C (mGluRl, mGluR5) and those that are negatively coupled to cyclic AMP formation via inhibition of adenyl cyclase (mGluR2-4, mGluR6-8). On the basis of sequence homology, the second-messenger mechanisms to which they are coupled, and pharmacological criteria, it has been useful to further divide mGluRs into three major groups. Group I corresponds to the mGluRs linked to PI turnover, whereas groups II (mGluR2, mGluR3) and III (mGluR4, mGluR6-8) encompass mGluRs linked to adenyl cyclase inhibition. In functional terms, the changes in second messengers induced by activation of metabotropic glutamate receptors can modulate the activity of Ca2+ and K+ channels and also directly affect the neurotransmitter release machinery, leading to changes in neuronal excitability and in the release of neurotransmitters at both glutamatergic and nonglutamatergic synapses. Generally, activation of group II mGluRs leads to presynaptic depression and consequent dampening of stimulus-evoked glutamate release, whereas activation of group III mGluRs inhibits the release of both GABA and glutamate. Of particular relevance to drug abuse, mGluRs can also modulate the release of dopamine, which has been most directly implicated in the rewarding aspects of many

Table 6

Some Selective Agonists and Antagonists of Metabotropic Glutamate Receptors

Compound Clinical status

Group I Agonists

5(-)-3,5-Dihydrophenylglycine (DHPG)

Quisqualate

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