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 activate d 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. Add itionally, these Ca2+-activated Cl- currents (I-Cl(Ca)) can be activat ed by raising intracellular Ca2+ through artificial experimental proce dures such as intracellular photorelease of Ca2+ from ''caged'' photol abile compounds (e.g. DM-nitrophen) or by treating cells with Ca2+ ion ophores. The potential changes that result from activation of Ca2+-act ivated Cl- channels are dependent on resting membrane potential and th e equilibrium potential for Cl-. Ca2+ entry during a single action pot ential is sufficient to produce substantial after potentials, suggesti ng that the activity of these Cl- channels can have profound effects o n cell excitability. The whole cell I-Cl(Ca)) can be identified by sen sitivity to increased Ca2+ buffering capacity of the cell, anion subst itution 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 remo ved from the intracellular environment. To date, there is no evidence in mammalian neurones to suggest these Ca2+-sensitive Cl- channels und ergo 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(C)l(Ca))) has been shown to be activated or prolonged as a resul t 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 ni flumic acid, derivatives of stilbene (4,4'diisothiocyanostilbene-2,2'- disulphonic acid, acetamido-4'-isothiocyanostilbene-2.2'-disulphonic a cid) and benzoic acid (5-nitro 2-(3-phenylpropylamino) benzoic acid), I-Cl(Ca)) are also sensitive to polyamine spider toxins and some of th eir analogues, particularly those containing the amino acid residue ar ginine. The physiological role of Ca2+-activated Cl- channels in neuro nes remains to be fully determined. The wide distribution of these cha nnels in the nervous system, and their capacity to underlie a variety of events such as sustained or transient depolarization or hyperpolari zations in response to changes in intracellular Ca2+ and variations in intracellular Cl- concentration, suggest the roles may be subtle, but important.