Aspects of calcium-activated chloride currents: A neuronal perspective

Ca²⁺-activated Cl^-channels are expressed in a variety of cell types, including central and peripheral neurones. These channels are activated by a rise in intracellular Ca²⁺ close to the cell membrane. This can be evoked by cellular events such as Ca²⁺ entry through voltage- and ligandgated channels or release of Ca²⁺ from intracellular stores. Additionally, these Ca²⁺-activated Cl^- currents (I_Cl(Ca)) can be activated by raising intracellular Ca²⁺ through artificial experimental procedures such as intracellular photorelease of Ca²⁺ from "caged" photolabile compounds (e.g. DM-nitrophen) or by treating cells with Ca²⁺ ionophores. The potential changes that result from activation of Ca²⁺-activated Cl^- channels are dependent on resting membrane potential and the equilibrium potential for Cl^-, Ca²⁺ entry during a single action potential is sufficient to produce substantial after potentials, suggesting that the activity of these Cl^- channels can have profound effects on cell excitability. The whole cell I_Cl(Ca) can be identified by sensitivity to increased Ca²⁺ buffering capacity of the cell, anion substitution studies and reversal potential measurements, as well as by the actions of Cl^- channel blockers. In cultured sensory neurones, there is evidence that the I_Cl(Ca) deactivates as Ca²⁺ is buffered or removed from the intracellular environment. To date, there is no evidence in mammalian neurones to suggest these Ca²⁺-sensitive Cl^- channels undergo a process of inactivation. Therefore, I_Cl(Ca) can be used as a physiological index of intracellular Ca²⁺ close to the cell membrane. The I_Cl(Ca) has been shown to be activated or prolonged as a result of metabolic stress, as well as by drugs that disturb intracellular Ca²⁺ homeostatic mechanisms or release Ca²⁺ from intracellular stores. In addition to sensitivity to classic Cl^- channel blockers such as niflumic acid, derivatives of stilbene (4,4′diisothiocyanostilbene-2,2′-disulphonic acid, 4-acetamido-4′-isothiocyanostilbene-2.2′-disulphonic acid) and benzoic acid (5-nitro 2-(3-phenylpropylamino) benzoic acid), I_Cl(Ca) are also sensitive to polyamine spider toxins and some of their analogues, particularly those containing the amino acid residue arginine. The physiological role of Ca²⁺-activated Cl^- channels in neurones remains to be fully determined. The wide distribution of these channels in the nervous system, and their capacity to underlie a variety of events such as sustained or transient depolarization or hyperpolarizations in response to changes in intracellular Ca²⁺ and variations in intracellular Cl^- concentration, suggest the roles may be subtle, but important.