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

Ted Begenisich,Tesuji Nakamoto,Catherine E Ovitt,Keith Nehrke,Carlo Brugnara,Seth L Alper,James E Melvin

doi:10.1074/jbc.m409627200

Abstract

Three broad classes of Ca(2+)-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.

Highlights

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
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 encoded by the Kcnn4 gene
The mouse Kcnn4 gene was inactivated by homologous recombination in embryonic stem cells

Summary

Introduction

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. The fluid-secreting acinar cells of the parotid gland express both IK and BK channels, raising questions about their particular respective roles. Kcnn null mice were of normal appearance and fertility, their parotid acinar cells expressed no IK channels, and their red blood cells lost K؉ permeability. 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 encoded by the Kcnn gene. Red blood cells have a high but latent passive permeability to Kϩ ions that is mediated by what is often called the Gardos channel [7] This channel has all the properties of, and is likely encoded by, the KCNN4 gene [4, 8]. Blocking the red blood cell IK channel with clotrimazole prevents erythrocyte dehydration in patients with sickle cell disease [9, 10] and in a mouse model of sickle cell disease [11, 12]

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