GABA-benzodiazepin-chloride channel

FIGURE 65.4 GABA-benzodiazepine-chloride channel complex. GABA = g-aminobutyric acid. 

In the retina, homomeric receptors consisting of the p-subunit represent a particular class of GABA-gated chloride channels. Their GABA site is insensitive to bicuculline and baclofen and they are not modulated by barbiturates or benzodiazepines. Due to these distinctive features, the receptors are sometimes termed GABAc receptors (Bormann 2000), although they are be considered a homomeric class of GABAa receptors (Barnard et al. 1998). 

Barbiturates also facilitate the actions of GABA at multiple sites in the central nervous system, but—in contrast to benzodiazepines—they appear to increase the duration of the GABA-gated chloride channel openings. At high... 

Perhaps the most well-known example is the acetylcholine receptor located on the postsynaptic membrane of the neuromuscular junction49 56 (Fig. 4-1). When bound by acetylcholine molecules, the receptor activates and opens a pore through the cell membrane, thereby increasing the permeability of the muscle cell to sodium.38 56 This action results in depolarization and excitation of the cell because of sodium influx. Another important example of a receptor-ion channel system is the gamma-aminobutyric acid (GABA)-benzodiazepine-chloride ion channel complex found on neuronal membranes in the central nervous sys-... 

Consequently, the presence of the GABA-benzodiazepine-chloride ion channel complex accounts for the specific mechanism of action of this class of sedative-hypnotics. By increasing the inhibitory effects at GABAergic synapses located in the reticular formation, benzodiazepines can decrease the level of arousal in the individual. In other words, the general excitation level in the reticular activating system decreases, and relaxation and sleep are enhanced. 

The benzodiazepine derivatives class of antianxiety agents shares the property of binding to a benzodiazepine receptor, part of the GABA receptor-chloride channel complex whose function it modulates allosterically. Not only the anxiolytic effects of the benzodiazepines, but also the anticonvulsant, sedative, or muscle relaxant effects seem to be mediated by the GABA-related mechanism. Besides the direct involvement of the GABA system, in parallel or more downstream to this, several other neurotransmitters such as serotonin have been suggested to participate in different aspects of benzodiazepine action. 

Suriclone, a cyclopyrrolone analogue of zopiclone, has similar pharmacology to the benzodiazepines, binding close to the same site of the GABA receptor-chloride channel complex. It is effective as an anxiolytic and has the notable advantages of minimal sedation and cognitive toxicity, and milder withdrawal effects than those of diazepam or lorazepam (1). Its withdrawal from further development is a mystery. 

Although it is chemically distinct to the benzodiazepines, zopiclone, a cyclopyrrolone, has similar pharmacology, binding close to the same site of the GABA receptor-chloride channel complex. 

Benzodiazepines all bind to a specific binding site on the gamma-aminobutyric acid (GABA) A chloride channel. The GABA chloride channel is a multi-subunit protein complex that is found in the plasma membrane of nerve cells in various parts of the CNS. When the neurotransmitter GABA binds to the chloride channel, the channel opens, allowing the influx of chloride ions into the cell. This causes hyperpolarization of the nerve cell and diminishes its response to excitatory input. The GABAa chloride channel is considered the major inhibitory system to neurotransmission in the CNS. 

The major inhibitory neurotransmitter in the cerebral cortex is y-aminobutyric acid (GABA). It attaches to neuronal membranes and opens chloride channels. When chloride flows into the neuron, it becomes hyperpolarized and less excitable. This mechanism is probably critical for shutting off seizure activity by controlling the excessive neuronal firing. Some antiepileptic drugs, primarily barbiturates and benzodiazepines, work by enhancing the action of GABA. 

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

---