Metabotropic glutamate receptors, in contrast to ionotropic glutamate receptors, do not form ion channels but instead affect intracellular chemical messenger systems. They couple via GTP-binding proteins ("G-proteins") to a variety of effectors such as ion channels and thus give glutamate, the major excitatory transmitter in the CNS, the ability to modulate processes involved in excitatory synaptic transmission. Therefore, excitatory synaptic transmission is regulated not only by the conventional GABAergic but also by the glutamatergic mechanisms themselves. Many metabotropic glutamate receptors are localized outside the immediate vicinity of transmitter release sites, thereby setting specific requirements for their activation, such as cooperation between synapses, burst activity, and glial involvement in the regulation of ambient glutamate levels.