CHLORIDE-CHANNEL ACTIVATORS lead to the opening of membrane chloride channels. Chemical agents and other influences (e.g. cell membrane stretch) that open or close chloride channels in the membrane have received much less study than the three cation channels. Studies have been hampered by the paucity of the sorts of selective chemical tools — particularly venoms and toxins — that have proved so valuable in dissecting the properties of individual cation channels. However, recently a number of chloride channels have been cloned and expressed, and this has facilitated studies of their individual properties. Further, the considerable prevalence of cystic fibrosis (CF), in which the core pathology is a failure to properly transport Cl” in all secretory epithelia, has stimulated research. Recently, this has led to the elucidation of much of the molecular pathology of this disease, to the level of the genomic location of mutants in epithelial cystic fibrosis transmembrane conductance regulator gene (CFTR). It transpires that CFTR is a substrate for PKA phosphorylation, a step in the activation pathway of one or more Cl+ channels, and is thought to be a cAMP-dependent chloride-conducting channel (Ic1)cAMP). This conductance can also be activated by genistein, levamisole and psoralens.
Calcium-activated chloride channels (CaCC), _ like the equivalent K+-current — is activated when there is Ca2+-mobilization within the cell, for instance, on activation of receptors coupled to the InsP3/DAG systems. This chloride channel provides the current commonly measured in oocytes as a means of detecting G-protein activation, on activation of experimentally expressed receptors. In smooth muscle, where the chloride equilibrium potential is typically more positive than the membrane potential; this current can cause depolarization that follows a rise in [Ca]1.
Maxi Cl- (Ic1(maxi) is a large conductance channel that is activated by G-proteins, and may be regulated by cell swelling, large voltage steps and GTPγS.
Voltage-gated chloride channels are found in many membranes. Recently, an expanding gene family called ClC has been recognized, at least some of which are voltage-gated. There are at least nine different ClC genes in mammals, several of which seem to be expressed ubiquitously, while others are expressed in a highly specific manner (e.g. the muscle-specific ClC-1 channel and the kidney-predominant ClC-5 channels). ClC chloride channels are structurally unrelated to other channel proteins, and have 12 putative transmembrane domains. They function as multimers with probably 4 subunits.Their properties are not yet fully explored, and specific activators or blockers are not yet developed They mainly are voltage-activated (but by depolarization or hyperpolarization depending on the channel) but some are also volume activated (also vide infra).
Volume-sensitive chloride channels are central to regulating cell volume in response to osmotic shock or nutrient uptake responses, especially in epithelial cells. A few are thought by some to be associated with the multidrug resistance gene (MDR-1 gene) product, which encodes the multidrug transporter protein beta-glycoprotein, an ATPase transporter capable of pumping a wide variety of hydrophobic chemotherapeutic agents out of the cell. The relationship between these channels, the various ATP-activated chloride currents observed on heart and gland (apparently via Β2-receptors) and the ClC family of channels is not entirely clear. However, the so-called VRAC (volume regulated anion channel) family can be activated by tyrosine phosphatase blockers, thrombin and intracellular ATP requirments. Also ClC-3 can be activated by swelling.
Ligand-gated channels in the form of heterooligomeric GABAA and glycine receptors with intrinsic chloride ion channels, have a widespread distribution in the central nervous system of vertebrates, and the entire nervous system of invertebrates The endogenous natural activators of these receptor channels are y-aminobutyric acid and glycine themselves, but a number of unnatural chemicals may activate or modulate them so they become more permeant to Cl” and so decrease membrane excitability. See GABA RECEPTOR AGONISTS; GLYCINE RECEPTOR AGONISTS.