FIGURE 21–7 Schematic diagram of a glutamate synapse. Glutamine is imported into the glutamatergic neuron (A) and converted into glutamate by glutaminase. The glutamate is then concentrated in vesicles by the vesicular glutamate transporter (VGLUT). Upon release into the synapse, glutamate can interact with AMPA and NMDA ionotropic receptor channels (AMPAR, NMDAR) and with metabotropic receptors (mGluR) on the postsynaptic cell (B). Synaptic transmission is terminated by active transport of the glutamate into a neighboring glial cell (C) by a glutamate transporter. It is converted into glutamine by glutamine synthetase and transported back into the glutamatergic axon terminal.
B. GABA and Glycine
Both GABA and glycine are inhibitory neurotransmitters, which are typically released from local interneurons. Interneurons that release glycine are restricted to the spinal cord and brain stem, whereas interneurons releasing GABA are present throughout the CNS, including the spinal cord. It is interesting that some interneurons in the spinal cord can release both GABA and glycine. Glycine receptors are pentameric structures that are selectively permeable to Cl –. Strychnine, which is a potent spinal cord convulsant and has been used in some rat poisons, selectively blocks glycine receptors.
GABA receptors are divided into two main types: GABAA and GABAB. Inhibitory postsynaptic potentials in many areas of the brain have a fast and slow component. The fast component is mediated by GABAA receptors and the slow component by GABAB receptors. The difference in kinetics stems from the differences in coupling of the receptors to ion channels. GABAA receptors are ionotropic receptors and, like glycine receptors, are pentameric structures that are selectively permeable to Cl –. These receptors are selectively inhibited by picrotoxin and bicuculline, both of which cause generalized convulsions. A great many subunits for GABAA receptors have been cloned; this accounts for the large diversity in the pharmacology of GABAA receptors, making them key targets for clinically useful agents (see Chapter 22). GABAB receptors are metabotropic receptors that are selectively activated by the anti-spastic drug baclofen. These receptors are coupled to G proteins that, depending on their cellular location, either inhibit Ca2+ channels or activate K+ channels. The GABAB component of the inhibitory postsynaptic potential is due to a selective increase in K+ conductance. This inhibitory postsynaptic potential is long-lasting and slow because the coupling of receptor activation to K+ channel opening is indirect and delayed. GABAB receptors are localized to the perisynaptic region and thus require the spillover of GABA from the synaptic cleft. GABAB receptors are also present on the axon terminals of many excitatory and inhibitory synapses. In this case, GABA spills over onto these presynaptic GABAB receptors, inhibiting transmitter release by inhibiting Ca2+ channels. In addition to their coupling to ion channels, GABAB receptors also inhibit adenylyl cyclase and decrease cAMP generation.