Aspects of calcium-activated chloride currents: A neuronal perspective

Roderick H. Scott, Kathy G. Sutton, Andrew Griffin, Simon R. Stapleton, Kevin P.M. Currie

Research output: Contribution to journalReview articlepeer-review

64 Scopus citations

Abstract

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 (ICl(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 ICl(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 ICl(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, ICl(Ca) can be used as a physiological index of intracellular Ca2+ close to the cell membrane. The ICl(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), ICl(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.

Original languageEnglish (US)
Pages (from-to)535-565
Number of pages31
JournalPharmacology and Therapeutics
Volume66
Issue number3
DOIs
StatePublished - 1995
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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