Excitatory Amino Acid Metabotropic Receptor Subtypes and Calcium Regulation

Calcium (Ca2+) possesses a pivotal role in a large variety of cellular processes. In neurons, it represents an essential step in the mechanisms triggering synaptic plasticity, long-term potentiation,lJ long-term cytoskeletal organization,h e x o c y t o ~ i s , ~ , ~ and delayed neurotoxicity.Y Considering all these distinct fundamental roles of Ca2+, one may logically suppose that they result from specific changes in intraccllular Ca2+ concentration, which differ in their amplitude, duration, and location. All these subcellular Ca2+ variations should be tightly regulated to avoid the emergence of uncontrolled mechanisms, often leading ultimately to cell death. Many systems contributc to this rcgulation, namcly, mcmbranc sodium (Na+)/Ca2+ cxchangcrs, Ca2+ pumps (Ca2+-ATPases), CaZ+ binding proteins, and Ca2+ channels. The later category could be divided into five main subtypes: voltage-dependent Caz + channels (VDCC), receptor-operated Ca2+ channels (ROC), G-protein-operated Ca2+ channel (GOC), second messenger-operated Ca2+ channels (SMOC), and finally Ca2+ release-activated channel (CRAC), as recently proposed'" (FIG. I ) . Glutamate (Glu), which is the main excitatory neurotransmitter in the brain, may dircctly or indirectly modulate most of thc above-mentioned Ca'+ channels. Its action occurs via two main classes of receptors, namely, the ionotropic and the metabotropic receptors as shown in FIGURE 2. lonotropic Glu receptors (iGluR) are composed o f subunit proteins, which form an integral ligand-gated ion channel. iGluR can be subdividcd into two main categories, thc N-mcthyl-D-aspartate (NMDA) receptors and the non-NMDA ones. The NMDA receptor family are receptorchannels, permeable to Ca2+ (ROC). The non-NMDA receptors, composed of a-amino-3-hydroxy-5-mcthyl-4-isoxazolc propionic acid (AMPA) rcccptors and kainic acid (KA) receptors, arc also receptor-channels, generally almost impermeable to Ca2+. The exception to this last statement is the existence of AMPA receptors lacking the GIuR2 subunit, which arc pcrmcablc to Ca'+. Thc activation of the non-NMDA receptors produces a depolarization, which opcns the VDCC. The second class of receptors, the metabotropic glutamate receptors (mGluR) are linked to G-proteins. Their stimulation generates the formation of second messengers and/or regulates ion channel function. Molecular cloning by cross-hybridization and polymerase chain reaction (PCR) has revealed the existencc of at least seven subtypes of mGluR.11-t6 The mGluR can be subdivided into three main subgroups according to DNA sequence similarities, receptor-associated signal transduction, and the agonist s e l e c t i v i t i e ~ ~ ~ (FIG. 2). In agreement with their high sequence