Structure, Gating and Basic Functions of the Ca2+-activated K Channel of Intermediate Conductance

Abstract

BackgroundThe 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.MethodsResearch and online content related to the structure, structure/function relationship, and physiological role of the KCa3.1 channel are reviewed.ResultsExpressed 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.ConclusionMuch 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.

A Compartmentalized Reduction in Membrane-Proximal Calmodulin Reduces the Immune Surveillance Capabilities of CD8+ T Cells in Head and Neck Cancer

“…Calmodulin (CaM) gene expression has been shown to be altered in TIL of breast cancer patients (Gu-Trantien et al, 2013). CaM is a signaling molecule that controls multiple T cell functions including KCa3.1 activity which is triggered by an increase in cytosolic Ca 2+ (Cahalan and Chandy, 2009;Sforna et al, 2018). CaM binds to the C-terminus of KCa3.1 and acts as a calcium sensor (Schumacher et al, 2001;Stocker, 2004;Adelman, 2016;Lee and Mackinnon, 2018;Sforna et al, 2018).…”

“…CaM is a signaling molecule that controls multiple T cell functions including KCa3.1 activity which is triggered by an increase in cytosolic Ca 2+ (Cahalan and Chandy, 2009;Sforna et al, 2018). CaM binds to the C-terminus of KCa3.1 and acts as a calcium sensor (Schumacher et al, 2001;Stocker, 2004;Adelman, 2016;Lee and Mackinnon, 2018;Sforna et al, 2018). CaM is constitutively bound to the channel in a Ca 2+ -independent manner (Schumacher et al, 2001;Stocker, 2004;Adelman, 2016;Lee and Mackinnon, 2018).…”

“…This pre-association allows for rapid channel gating when the intracellular Ca 2+ concentration changes (Adelman, 2016). When intracellular Ca 2+ increases, CaM undergoes conformational changes and causes the channel to open (Schumacher et al, 2001;Stocker, 2004;Lee and Mackinnon, 2018;Sforna et al, 2018). While it is known that CaM levels increase in activated healthy T cells, its protein abundance and functional implications in T cells of cancer patients, to our knowledge, have not yet been investigated (Colomer et al, 1993).…”

A critical role of the KCa3.1 channel in mechanical stretch‐induced proliferation of rat bone marrow‐derived mesenchymal stem cells

“…Compelling evidence shows that mechanical stimulation is an important factor regulating MSC functions, including proliferation, but the underlying mechanism is far from understood . K Ca 3.1 channel, also known as KCNN4, IK Ca and SK4, is an intermediate‐conductance member of the Ca 2+ ‐activated K + channel family and is widely expressed in both excitable and non‐excitable cells, where it plays an important role in various cell functions . Interestingly, there is increasing evidence to support the K Ca 3.1 channel is engaged in MSC proliferation .…”

“…and non-excitable cells, where it plays an important role in various cell functions. 8 Interestingly, there is increasing evidence to support the K Ca 3.1 channel is engaged in MSC proliferation. [9][10][11] Previous studies showed that the expression of the K Ca 3.1 channel in human umbilical vein endothelium cells was up-regulated by fluid flow-induced shear stress, or its channel activity in vascular smooth muscle cells was enhanced by hypotonic solution-induced membrane stretch.…”