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

180209 Data PE SK4icon sp96    SyncroPatch 384/768 PE (a predecessor model of SyncroPatch 384/768i) 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.

Application Notes

KCa3.1 - "Modulation of hKCa3.1 by internal Ca2+ performed on Nanion’s Patchliner"

icon pl   Patchliner application note:   logo pdf   (0.6 MB)
Cells were kindly provided by Charles River.

Publications

2019 - GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner

icon pl   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

icon sp96  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

icon pl  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

icon pl  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.

Webinars

27.06.2017 | Webinar: New Dynamics in Automated Patch Clamp

icon pl   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

icon sp96   SyncroPatch 384PE (a predecessor model of SyncroPatch 384i),   icon pl   Patchliner,   icon pap   Port-a-Patch Webinar

Date: November 20. 2018, 4:00 PM CET (11:00 AM EDT)

181120 event image Relevance project Webinar

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.

 

 

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