KCa3.1 | IK | SK4 | Intermediate Conductance Calcium-activated Potassium Channel Protein 4
Family:
Calcium- and sodium-activated Potassium channels
Members:
Today, eight human calcium-activated channels are known: KCa1.1 (also known as BK or Maxi-K), KCa2.1 (also known as SK1), KCa2.2 (also known as SK2), KCa2.3 (also known as SK3) , KCa3.1 (also known as IK or SK4), KCa4.1, KCa4.2, KCa5.1
Topology:
KCa channels are made up of two different subunits, alpha and beta. The alpha subunit contains six or seven trans-membrane regions and forms homo- or heter-tetramers. The beta subunit has a regulative function and contains 2 trans-membrane regions.
Regulation:
This family of ion channels is, for the most part, activated by intracellular Ca2+. However, some of these channels (the KCa4 and KCa5 channels) are responsive instead to other intracellular ligands, such as Na+, Cl−, and pH. Furthermore, multiple members of family are both ligand and voltage activated.
KCa3.1 Background Information
KCa3.1 (aka SK4 or Gardos channel) is part of a potentially heterotetrameric voltage-independent potassium channel that is activated by intracellular calcium. Activation is followed by membrane hyperpolarization, which promotes calcium influx. KCa3.1 is involved in regulating the hyperpolarized (negative) membrane potential which is critical for immune cell activation. In addition to functions in cell cycle progression and cellular proliferation, KCa3.1 channels play an important immunoregulatory role, including participation in pathologic mechanisms that are associated with the inflammatory and proliferative cascades that characterise autoimmune diseases such as rheumatoid arthritis. KCa3.1 is involved in lymphocyte activation, and in the proliferation and migration of T cells, B cells, mast cells, macrophages and fibroblasts.
Gene:
KCNN4
Human Protein:
UniProt O15554
Tissue:
Widely expressed in non-excitable tissues (absent in brain, skeletal muscle and heart), expressed in T and B lymphocytes, erythrocytes, Macrophages and monocytes
Function/ Application:
Immune regulation, cellular signalling, volume regulation in erythrocytes, involved in fluid and salt transport in secretory epithelia
Pathology:
Dehydrated hereditary stomatocytosis 2 (DHS2), hereditary xerocytosis, Diamond-Blackfan anemia, Sickle cell anemia,
Pharmacology:
As an inflammation-relevant drug target, KCa3.1 modulators are being investigated for potential in the treatment of asthma and fibroproliferative disorders, and for immunosuppressant efficacy.
Interaction:
Calmodulin, nucleoside diphosphate kinase B (NDPK-B)
Modulator:
Clotrimazole, charybdotoxin, riluzole, nitrendipine, TRAM-34
Assays:
Patch clamp
Recommended Reviews:
Kaczmarek et al. (2017) International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels. Pharmacol Rev 69(1):1-11
Data and Applications
KCa3.1 (SK4) - Activation by Perfusion of free internal Calcium
SyncroPatch 384/768 PE (a predecessor model of SyncroPatch 384) data and applications:
Cells were kindly provided by Charles River.
Screenshots of the PatchControl 384 software are showing KCa3.1 raw traces and according time plots (online analysis) to a voltage ramp from -120 mV to + 60 mV over 200 ms. The application of internal Ca2+ is indicated by the yellow bar. The current increased upon application of internal Ca2+ reaching a peak within 1-2 min after the start of the perfusion. Five minutes of stable KCa3.1 current was recorded prior the channel was inhibited by cumulative additions of external Ba2+; first partly (1 mM Ba2+) and then completely (5 mM Ba2+). The recording was performed with perfectly high success rates in whole cell configuration on a multi hole chip (4 holes per well) using the SyncroPatch 384PE (a predecessor model of SyncroPatch 384).
Application Notes
KCa3.1 - "Modulation of hKCa3.1 by internal Ca2+ performed on Nanion’s Patchliner"
Patchliner application note: 
(0.6 MB)
Cells were kindly provided by Charles River.
Webinars
28.04.2020 | Webinar: Validation and optimization of automated patch clamp voltage-gated Ca2+ channel assays
Patchliner Webinar
Date: April 28. 2020, 4:00 PM CET (10:00 AM EDT)
Marc will outline the development, optimization and validation of a range of voltage-gated Ca2+ channel assays on the Patchliner automated patch clamp platform that were subsequently used in an 8 year drug discovery collaboration between Metrion Biosciences and a german pharma company.
Speakers:
Dr. Marc Rogers (Chief Scientific Officer, Metrion Biosciences)
Dr. András Horváth (Application Scientist, Nanion Technologies)
27.06.2017 | Webinar: New Dynamics in Automated Patch Clamp
Patchliner
This webinar shows new applications on dynamic patch clamp of iPSC-derived cardiomyocytes and introduces an assay on KCa3.1 expressed in erythrocytes
20.11.2018 | Webinar: The RELEVANCE of ion channel interplay – Voltage-activated channels in non-excitable cells
SyncroPatch 384PE (a predecessor model of SyncroPatch 384i), Patchliner, 
Port-a-Patch Webinar
Date: November 20. 2018, 4:00 PM CET (11:00 AM EDT)
The Webinar focuses on the automated patch clamp assay development for the study of red blood cells in health and disease and the RELEVANCE project, an international consortium of 13 partners from academia, diagnostic labs, blood supply centers, and small companies that combines basic and translational research to improve prognostic, diagnostic and therapeutic approaches on red blood cell function in health and disease. To this end, Nanion contributes assays for the electrophysiological characterization of healthy and patient-derived red blood cells.
07.09.2021 | Webinar: Automated patch clamp assay development for the study of red blood cells (RBCs) in health and disease
SyncroPatch 384, Patchliner, Port-a-Patch Webinar
Date: September 07. 2021, 4:00 PM CEST (10:00 AM EDT)
Abstract:
Calcium (Ca2+) is a universal signalling molecule and is critically important in regulating many physiological functions and survival of RBCs. Amongst others, intracellular Ca2+ controls cell volume and deformability. This process plays a substantial role in RBCs since their volume needs to adapt when passing blood vessel constrictions during the flow. Excessive Ca2+ uptake also leads to accelerated cell clearance causing anaemia.
Therefore, studying Ca2+ regulation is crucial to understand RBC diseases. Piezo1, KCa3.1 (Gardos channel) and NMDA receptors are three channels present in the RBC membrane and critical for Ca2+ regulation.
We developed functional assays to measure these channels in healthy and diseased RBCs populations using electrophysiological tools, contributing to the characterization of RBC diseases.
Publications
2020 - Structural basis of the potency and selectivity of Urotoxin, a potent Kv1 blocker from scorpion venom
Patchliner publication in Biochemical Pharmacology (2020)
Authors:
Luna-Ramirez K., Csoti A., McArthur J.R., Chin Y.K.Y., Anangi R., del Carmen Najera R., Possani L.D., King G.F., Panyi G., Yu H., Adams D.J., Finol-Urdaneta R.K.
2019 - GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner
Patchliner publication in Gut (2019)
Authors:
Jiang S.H., Zhu L.L., Zhang M., Li R.K., Yang Q., Yan J.Y., Zhang C., Yang J.Y., Dong F.Y., Dai M., Hu L.P., Li J., Li Q., Wang Y.H., Yang X.M., Zhang Y.L., Nie H.Z., Zhu L., Zhang X.L., Tian G.A., Zhang X.X., Cao X.Y., Tao L.Y., Huang S., Jiang Y.S., Hua R., Qian Luo K., Gu J.R., Sun Y.W., Hou S., Zhang Z.G.
2017 - Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions
SyncroPatch 768PE (a predecessor model of SyncroPatch 384/768i) publication in Nature Communications (2017)
Authors:
Chiang E.Y., Li T., Jeet S., Peng I., Zhang J., Lee W. P., DeVoss J., Caplazi P., Chen J., Warming S., Hackos D.H., Mukund S., Koth C.M., Grogan J.L.
2017 - 'Gardos Channelopathy': a variant of hereditary Stomatocytosis with complex molecular regulation
Patchliner publication in Scientific Reports (2017)
Authors:
Fermo E., Bogdanova A., etkova-Kirova P., Zaninoni A., Marcello A.P., Makhro A., Hänggi P., Hertz L., Danielczok J., Vercellati C., Mirra N., Zanella A., Cortelezzi A., Barcellini W., Kaestner L., Bianchi P.
2016 - Human T cells in silico: Modelling their electrophysiological behaviour in health and disease
Patchliner publication in Journal of Theoretical Biology (2016)
Authors:
Ehling P., Meuth P., Eichinger P., Hermann A.M., Bittner S., Pawlowski M., Pankratz S., Herty M., Budde T., Meuth S.G.