Recombinant Human Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4) Protein

Function

Intermediate conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening (PubMed:10026195, PubMed:10961988, PubMed:11425865, PubMed:15831468, PubMed:17157250, PubMed:18796614, PubMed:26148990, PubMed:9326665, PubMed:9380751, PubMed:9407042). The current is characterized by a voltage-independent activation, an intracellular calcium concentration increase-dependent activation and a single-channel conductance of about 25 picosiemens (PubMed:9326665, PubMed:9380751, PubMed:9407042). Also presents an inwardly rectifying current, thus reducing its already small outward conductance of potassium ions, which is particularly the case when the membrane potential displays positive values, above + 20 mV (PubMed:9326665, PubMed:9380751, PubMed:9407042). Controls calcium influx during vascular contractility by being responsible of membrane hyperpolarization induced by vasoactive factors in proliferative vascular smooth muscle cell types (By similarity). Following calcium influx, the consecutive activation of KCNN4 channel leads to a hyperpolarization of the cell membrane potential and hence an increase of the electrical driving force for further calcium influx promoting sustained calcium entry in response to stimulation with chemotactic peptides (PubMed:26418693). Required for maximal calcium influx and proliferation during the reactivation of naive T-cells (PubMed:17157250, PubMed:18796614). Plays a role in the late stages of EGF-induced macropinocytosis through activation by PI(3)P (PubMed:24591580)

Subcellular Location

Cell membrane (Multi-pass membrane protein); Cell projection, ruffle membrane

Disease Association

Dehydrated hereditary stomatocytosis 2 (DHS2) : An autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. Affected individuals typically manifest mild to moderate compensated hemolytic anemia, with an increased erythrocyte mean corpuscular hemoglobin concentration and a decreased osmotic fragility, both of which reflect cellular dehydration. Their red cells exhibit a panel of various shape abnormalities such as elliptocytes, hemighosts, schizocytes, and very rare stomatocytic cells. Complications such as splenomegaly and cholelithiasis, resulting from increased red cell trapping in the spleen and elevated bilirubin levels, respectively, may occur. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Widely expressed in non-excitable tissues

Subunit

Homodimer (PubMed:29953543). Homotetramer (PubMed:29724949). Heterotetramer of potassium channel proteins (Probable). Interacts with MTMR6; this interaction leads to selective dephosphorylation of PI(3)P in a lipid microdomain adjacent to KCNN4, resulting in a decrease of intermediate conductance calcium-activated potassium channel activity (PubMed:15831468). Interacts (via the C-tail domain) with CALM1; the calmodulin binding is constitutive, does not require calcium and mediates calcium-dependent gating and four calmodulin molecules bind to one channel tetramer (PubMed:10026195)

• Joiner W.J. et al. hSK4, a member of a novel subfamily of calcium-activated potassium channels. — Proc. Natl. Acad. Sci. U.S.A. (1997)
• Ishii T.M. et al. A human intermediate conductance calcium-activated potassium channel. — Proc. Natl. Acad. Sci. U.S.A. (1997)
• Logsdon N.J. et al. A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes. — J. Biol. Chem. (1997)
• Ghanshani S. et al. Human calcium-activated potassium channel gene KCNN4 maps to chromosome 19q13.2 in the region deleted in diamond-blackfan anemia. — Genomics (1998)
• Ghanshani S. et al. Up-regulation of the IKCa1 potassium channel during T-cell activation. Molecular mechanism and functional consequences. — J. Biol. Chem. (2000)
• Mazzone J.N. et al. Characterization of calcium-activated potassium channels in human myometrium. (JUN-)
• Kalnine N. et al. Cloning of human full-length CDSs in BD Creator(TM) system donor vector. (MAY-)
• Mural R.J. et al. PubMed: CI-5GBDQ6B103N1E (JUL-)