Chloride ion channels

Gamma aminobutyric acid (GABA) receptors are located on the postsynaptic membranes of inhibitory synapses of both vertebrates and insects and contain within their membrane-spanning structure a chloride ion channel. They are found in both vertebrate brains and invertebrate cerebral ganglia (sometimes referred to as brains) as well as in insect muscles. Particular attention has been given to one form of this receptor—the GABA-A receptor—as a target for novel insecticides (Eldefrawi and Eldefrawi 1990). It is found both in insect muscle and vertebrate brain. The remainder of this description will be restricted to this form. 

Experimentally all GABA antagonists induce convulsions. These include the genuine receptor antagonist bicuculline, which competes with GABA for its recognition site on the GABAa receptor and picrotoxin, which binds to a different site more closely related to the chloride ion channel. 

The gene product is termed cystic fibrosis transmembrane conductance regulator (CFTR), and it codes for a chloride ion channel. It may also carry out additional (as yet undetermined) functions. 

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]. 

In regards to necrosis, it is clear that the old adage an ounce of prevention is worth a pound of cure applies. Agents that stabilize ion homeostasis have proved to be effective in preventing necrosis in cell culture studies. For example, drugs that activate plasma membrane potassium ion channels or chloride ion channels can prevent membrane depolarization and so inhibit sodium and calcium ion influx. Agents that prevent large sustained increases in intracellular free calcium levels can also prevent neuronal... 

Burr SA, Ray DE (2004) Structure-activity and interaction effects of 14 different pyrcthroids on voltage-gated chloride ion channels. Toxicol Sci 77 341-346... 

The main action of BZs occurs at the y-aminobuteric acid A (CABAa) receptors. The CABA receptors have been classified into three subtypes, CABA, CABAg, and CABA. The CABAg slow receptors are composed of seven transmembrane subunits that activate second messenger systems. CABA and CABA receptors mediate fast synaptic inhibition via transmittergated chloride ion channels (Chebib and Johnston, 1999). Each CABA and CABA receptor consists of five subunits with four transmembrane domains, which combine together to form a chloride channel (Chebib and Johnston, 1999). 

Morrow LA, Pace JR, Purdy RH, et al Characterization of steroid interactions with g-aminobutyiic acid receptor-gated chloride ion channels evidence for multiple steroid recognition sites. Mol Pharmacol 37 226-229, 1990... 

Benzodiazepines facilitate inhibition by y-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. The benzodiazepine receptor is a subtype of the GABA receptor. Activation of the benzodiazepine receptor facilitates the action of endogenous GABA, which results in the opening of chloride ion channels and a decrease in neuronal excitability. Benzodiazepines act rapidly because ion channels can open and close relatively quickly, in contrast to the slower onset of action that occurs with G protein-linked receptors. 

Because alcohol and barbiturates also act, in part, via the GABA receptor-mediated chloride ion channel, benzodiazepines show cross-tolerance with these substances. Thus, benzodiazepines are used frequently for treating alcohol or barbiturate withdrawal and detoxification. Alcohol and barbiturates are more dangerous than benzodiazepines because they can act directly at the chloride ion channel at higher doses. In contrast, benzodiazepines have no direct effect on the ion channel the effects of benzodiazepines are limited by the amount of endogenous GABA. 

Buspirone is a partial agonist at serotonin type 1A (5-HTj ) receptors. Unlike benzodiazepines, barbiturates, and alcohol, buspirone does not interact with the GABA receptor or chloride ion channels. Thus, it does not produce sedation, interact with alcohol, impair psychomotor performance, or pose a risk of abuse. There is no cross-tolerance between benzodiazepines and buspirone, so benzodiazepines cannot be abruptly replaced with buspirone. Likewise, buspirone cannot be used to treat alcohol or barbiturate withdrawal and detoxification. Like the antidepressants, buspirone has a relatively slow onset of action. 

Ivermectin binds selectively and with high affinity to glutamate gated chloride ion channels in invertebrate nerve and muscle cells. This leads to an increase in the permeability of cell membrane to chloride ions with hyperpolarization of nerve of muscle cell, resulting in paralysis and death of the parasite. 

A model of the GABA receptor-chloride ion channel macromolecular complex. A hetero-oligomeric glycoprotein, the complex... 

The components of the GABAa receptor-chloride ion channel macromolecule that function as benzodiazepine binding sites... 

Now it is probably no coincidence that in addition to occupying the benzodiazepine receptor site on the chloride ion channel protein, these remarkable drugs can also occupy the sedation-convulsant receptor of the same protein. Sedation with benzodiazepines thus goes hand in hand with anticonvulsant power—as if the two processes had some deep mediating mechanism in common with each other. What could that be ... 

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