Cl- channels

In many epithelia Cl is transported transcellularly. Cl is taken up by secondary or tertiary active processes such as Na 2Cl K -cotransport, Na Cl -cotransport, HCOJ-Cl -exchange and other systems across one cell membrane and leaves the epithelial cell across the other membrane via Cl -channels. The driving force for Cl -exit is provided by the Cl -uptake mechanism. The Cl -activity, unlike that in excitable cells, is clearly above the Nernst potential [15,16], and the driving force for Cl -exit amounts to some 2(f-40mV. 

The regulation of epithelial Cl -channels has been examined in many laboratories, and these studies have been intensified with the recognition that the Cl -channel regulation in epithelia is defective in a very common and clinically serious inherited disease, namely cystic fibrosis [17,18]. Efforts in this direction have not yet arrived at coherent concepts, and many published models [19-22] may have to be modified or revised. 

The present chapter will address the following issues (1) a very brief overview on the properties of the different types of Cl -channels in the various mammalian cells (2) a short summary on what is known of Cl channels on a molecular basis (3) a discussion of pharmacological agents blocking the various Cl -channels and (4) a specific section dealing with the regulation of epithelial and maybe other Cl -channels. This entire area has been reviewed rather extensively in the recent past. A large number of references will be provided in order to keep this text concise. The entire field of Cl -channels in the central nervous system will only be touched upon to compare these channels to the Cl -channels in apolar cells and epithelia. 

In the following the Cl -channels will be subdivided into those of the central nervous system, of muscle and Torpedo electroplax, of apolar non-excitable cells and of epithelia. 

Other neuronal Cl -channels are Ca -controlled. Increases in cytosolic Ca enhances the probability of these channels being open [26,27]. These channels stabilize the membrane voltage by clamping it towards the Cl -equilibrium potential. Such channels have been found, e.g., in cultured mouse spinal neurones and in molluscan neurones. They subserve the repolarization phenomena and hence assist Ca -activated -channels. Their conductance is in the small to intermediate range. They are usually gated by depolarization. 

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The newest molecular addition to Cl- channels are bestrophins [5]. There are four different bestrophin isoforms in humans. Mutations in Bestl cause Best macular dystrophy, hence their name. All four isoforms induce chloride currents when expressed heterologously. Although they show a dependence on intracellular calcium, their biophysical properties differ from Ca-activated chloride currents typically observed in native cells. Mutagenesis experiments changed the activation of currents and induced slight changes in ion selectivity, lending support to the hypothesis that bestrophins themselves are Cl- channels. 

Lubiprostone, a drug used for treating obstipation, has been claimed to be an activator of C1C-2. This is based on a single paper showing activation by lubiprostone of currents thought to represent C1C-2. These currents, however, differ starkly from typical C1C-2 currents. Furthermore, C1C-2 is located in basolateral membranes of the intestine. This localization is incompatible with the hypothesis that its activation increases intestinal chloride and fluid secretion. Thus, the claim that lubiprostone is a Cl- channel activator must be subject to considerable doubt. 

The GABAA-receptor and the glycine receptor are Cl-channels (Table 1). When they open at a resting membrane potential of about -60 mV, the consequence is an entry of Cl-, hyperpolarization and an inhibitory postsynaptic potential (DPSP Fig. 1). 

Von Keyserlingk, H.C. and Willis, R.J. (1992). The GABA-activated CL channel in insects as a target for insecticide action—a physiological study. In D. Otto and B. Weber (Eds.) Insecticides Mechanism of Action and Resistance. Andover, U.K. Intercept. 

As outlined above (see also Chapter 9), these drugs have been found to influence the Cl channel of the GABAa receptor. Phenobarbitone acts directly to prolong its... 

ILLEK B, FISCHER H, SANTOS G F, WIDDICOMBE J H, MACHEN T E and REENSTRA W W (1995) cAMP-independent activation of CFTR Cl channels by the tyrosine kinase inhibitor genistein. ./Physiol. 268 (4 Ptl) C886-C893. 

In previous reviews on this matter by Gogelein [9] and myself [10] it has been pointed out that the Cl -channels of the central nervous system and of skeletal muscle are distinct from those of non-excitable cells. The latter entity is in itself obviously heterogeneous with respect to its occurrence and function. In apolar as well as in polarized cells Cl -channels may be involved in volume regulation. As a simple rule gating of K" - and Cl -channels is likely to occur whenever cell volume has to be down-regulated [11], as is the case in regulatory volume decrease of cell volume. A simple means to induce this phenomena is the exposure of cells to hypoosmolar solutions [12]. For example Cl -channels play an important role in... 

Cl -channels, which serve to take up Cl when the membrane voltage is depolarized, e.g., by an increase in ambient K -concentration, other GABA-sensitive Cl -channels have been found in recent studies [29]. The functional role of these channels has yet to be defined. 

Cl -channels are also present in neuroendocrine cells such as the AtT-20 pituitary cell line [30]. Ca -dependent and voltage-activated slow Cl -currents were found. These Cl -currents could subserve a role comparable to that of Cl -currents in renin-secreting cells or mast cells [13,14]. Along these lines, it has been speculated that the slow Cl inward currents may influence the firing rate of these neuroendocrine cells [30]. 

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