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

The KCa3.1 channel is the intermediate-conductance member of the Ca2+-activated K channel superfamily. 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. Upon Ca2+ binding, the KCa3.1 channel activates with high affinity 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. This paper aims at illustrating the main structural, biophysical and modulatory properties of the KCa3.1 channel, and at providing an account of experimental data on its role in volume regulation and Ca2+ signals.