Structure, gating and basic functions of the Ca²⁺-activated K channel of intermediate conductance

Background: The KCa3.1 channel is the intermediate-conductance member of the Ca²⁺-activated K channel superfamily. It is widely expressed in excitable and non-excitable cells, where it plays a major role in a number of cell functions. This paper aims at illustrating the main structural, biophysical and modulatory properties of the KCa3.1 channel, and providing an account of experimental data on its role in volume regulation and Ca²⁺ signals. Methods: Research and online content related to the structure, structure/function relationship, and physiological role of the KCa3.1 channel are reviewed. Results: Expressed in excitable and non-excitable cells, the KCa3.1 channel is voltage independent, its opening being exclusively gated by the binding of intracellular Ca²⁺ to calmodulin, a Ca²⁺-binding protein constitutively associated with the C-terminus of each KCa3.1 channel α subunit. The KCa3.1 channel activates upon high affinity Ca²⁺ binding, and in highly coordinated fashion giving steep Hill functions and relatively low EC50 values (100-350 nM). This high Ca²⁺ sensitivity is physiologically modulated by closely associated kinases and phosphatases. The KCa3.1 channel is normally activated by global Ca²⁺ signals as resulting from Ca²⁺ released from intracellular stores, or by the refilling influx through store operated Ca²⁺ channels, but cases of strict functional coupling with Ca²⁺-selective channels are also found. KCa3.1 channels are highly expressed in many types of cells, where they play major roles in cell migration and death. The control of these complex cellular processes is achieved by KCa3.1 channel regulation of the driving force for Ca²⁺ entry from the extracellular medium, and by mediating the K+ efflux required for cell volume control. Conclusion: Much work remains to be done to fully understand the structure/function relationship of the KCa3.1 channels. Hopefully, this effort will provide the basis for a beneficial modulation of channel activity under pathological conditions.