Despite myriad challenges, clinicians see room for progress.
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Rapid signals at the neuromuscular junction and at synapses between neurons are carried by small molecules, called neurotransmitters, that are released from the presynaptic terminal and bind to ligand-gated ion channels in the postsynaptic membrane. When transmitter binds, a small pore opens through which ions flow, resulting in a transient depolarization or hyperpolarization of the membrane and translating the chemical signal into an electrical one. The transmitters at the neuromuscular junction, and at excitatory synapses in the central nervous system, are acetylcholine and glutamate, respectively. Inhibitory signals are carried by two major transmitters: glycine, predominantly in the spinal cord, and γ-aminobutyric acid, or GABA, predominantly in the brain.
Receptors for these transmitters are important targets for drugs used to treat mental disorders, or to modulate sleep and mood. In particular, benzodiazepine-related drugs, such as Valium, Halcion, and Xanax, which are widely used for the treatment of anxiety and insomnia, appear to act by binding directly to a specific site on the GABA type A (GABAA) receptor, the principal GABA-gated ion channel (1, 2). Molecular biologists have spent much productive effort over the last decade working out the molecular structures of receptors for each of the major transmitters, while biophysicists have unraveled the detailed kinetics of transmitter binding and gating (1, 3, 4). The pharmaceutical industry concentrates enormous resources on determining the specificity and physiological consequences of binding of pharmacological agents to these receptors.
In recent years, many researchers have turned to a new issue governing receptor function: What is the immediate protein environment of the receptors, and how does that environment influence receptor function at different synapses? Receptors for the rapid transmitters are not distributed randomly over the surface of the membrane. Rather, they are “targeted” to the postsynaptic membrane and are thus concentrated adjacent to …
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