Physiological Roles of the Intermediate Conductance, Ca2+-activated Potassium Channel Kcnn4

Abstract

Three broad classes of Ca2؉ -activated potassium channels are defined by their respective single channel conductances, i.e. the small, intermediate, and large conductance channels, often termed the SK, IK, and BK channels, respectively. SK channels are likely encoded by three genes, Kcnn1-3, whereas IK and most BK channels are most likely products of the Kcnn4 and Slo (Kcnma1) genes, respectively. IK channels are prominently expressed in cells of the hematopoietic system and in organs involved in salt and fluid transport, including the colon, lung, and salivary glands. IK channels likely underlie the K ؉ permeability in red blood cells that is associated with water loss, which is a contributing factor in the pathophysiology of sickle cell disease. IK channels are also involved in the activation of T lymphocytes. The fluid-secreting acinar cells of the parotid gland express both IK and BK channels, raising questions about their particular respective roles. To test the physiological roles of channels encoded by the Kcnn4 gene, we constructed a mouse deficient in its expression. Kcnn4 null mice were of normal appearance and fertility, their parotid acinar cells expressed no IK channels, and their red blood cells lost K ؉ permeability. The volume regulation of T lymphocytes and erythrocytes was severely impaired in Kcnn4 null mice but was normal in parotid acinar cells. Despite the loss of IK channels, activated fluid secretion from parotid glands was normal. These results confirm that IK channels in red blood cells, T lymphocytes, and parotid acinar cells are indeed encoded by the Kcnn4 gene. The role of these channels in water movement and the subsequent volume changes in red blood cells and T lymphocytes is also confirmed. Surprisingly, Kcnn4 channels appear to play no required role in fluid secretion and regulatory volume decrease in the parotid gland.It has become clear that multiple types of Ca 2ϩ -activated potassium channels underlie a wide range of distinct physiological processes. Physiological and pharmacological analyses have subdivided Ca 2ϩ -activated potassium channels into three groups, i.e. the small, intermediate, and large conductance channels, often termed SK, 1 IK, and BK channels, respectively. IK channels, as their designation implies, have a single channel conductance intermediate between the SK and BK channels. These three functional groups have rather distinct pharmacological profiles, and SK, IK, and BK channels can be specifically blocked by apamin, clotrimazole, and paxilline, respectively. SK and IK channels are encoded by four genes of the KCNN gene family. The three SK channels, KCNN1-3, share ϳ70 -75% amino acid identity. The IK channel KCNN4 is encoded by a protein sharing only ϳ40% amino acid identity with each of the three SK channels, KCNN1-3.

Renal fibrosis is attenuated by targeted disruption of K Ca 3.1 potassium channels

“…Cytotoxic or proapoptotic actions potentially arising from K Ca 3.1 blockade by TRAM-34 were not observed. Although our data provide evidence for a cell cycle arrest in G 0 /G 1 , we cannot exclude additional effects of K Ca 3.1 inhibition at other points of the cell cycle, particularly those involving precise cell volume regulation (38). In any case, induction of K Ca 3.1 might constitute an important step for the initiation of renal fibroblast proliferation in response to mitogenic and profibrotic factors.…”

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

“…Median survival rates of the SK4 KO mice tend to result in a better outcome, but this tendency did not reach statistical significance. As SK4 channels are known to be important determinants in the activation of T and B cells (Begenisich et al ., 2004; Kang et al ., 2014; Xu et al ., 2014), decreased tumour formation in SK4 KO mice may be masked by the inability of the SK4‐deficient immune system to recognize and/or control tumorigenesis in breast cancer. To prove this hypothesis, we took a different approach and established an orthotopical transplantation model.…”

Blockage of intermediate-conductance-Ca2+-activated K+ channels inhibits progression of human endometrial cancer

“…Inhibition of the IKCa1 channel activity suppresses proliferation of pancreatic cancer cells (Jager et al, 2004). The activation of IKCa1 channels is Ca 2 þ -dependent with little or no voltage dependency (Nehrke et al, 2003;Begenisich et al, 2004). In both AT2.1 and MatLyLu rat prostate cancer cell lines, IKCa1 current densities are comparable to those found in fibroblasts transfected with oncogenic Ras or Raf (Rane, 2000).…”