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Physiological functions of the regulatory potassium channel subunit KCNE1

Institut für Physiologie, Universität Hamburg, 20246 Hamburg, Germany

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POTASSIUM (K⁺) channels are present in nearly all cells, where they play a key role in regulating cell excitability and epithelial transport. Alterations of their function are involved in numerous regulatory processes, ranging from modulating orthograde and retrograde propagation of dendritic potentials in the brain to insulin secretion in pancreatic -cells. Molecular analysis has shown that K⁺ channels consist of pore-forming -subunits that are encoded by at least 80 different specific mRNAs. These -subunits coassemble to form homo- or heteromultimeric channels. Additionally, they can associate with -subunits that alter their biophysical function and pharmacological sensitivity. Overall, this results in a bewildering number of possible structurally distinct K⁺ channels. So how can we ascribe specific physiological and pathophysiological roles to single K⁺ channel genes? Several recent investigations just succeeded in reaching this goal by combining analysis of channel expression pattern, targeted gene disruption in mice, and genetic linkage studies in humans. A striking example of this approach is reviewed by Warth and Barhanin (14), who describe in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology the diverse physiological functions exerted by the K⁺ channel -subunit KCNE1.

The discovery and subsequent biophysical and physiological analysis of KCNE1 provide a fascinating tale of scientific discovery. KCNE1 was one of the very first K⁺ channel genes to be cloned (12). It encodes a small membrane protein that consists of only 130 amino acids (for that reason, it was originally named minK). Because Xenopus oocytes expressing KCNE1 mRNA display slowly activating voltage-dependent K⁺ currents, KCNE1 was initially assumed to be a pore-forming channel protein. This concept seemed to be confirmed by site-directed mutagenesis studies, which showed that single amino acid changes alter ion selectivity, open-channel block, and modulation by protein kinase C (3, 6). KCNE1, however, has neither the P region nor signature sequence that characterizes the pore-forming subunits of all known K⁺ channel proteins. In 1996, two independent groups eventually demonstrated that KCNE1 functions as a modulatory -subunit of the pore-forming -subunit KCNQ1 (2, 9).

Coexpression of KCNE1 and KCNQ1 induces a current with characteristics nearly identical to the repolarizing cardiac current I_Ks. Shortly after the demonstration of KCNE1/KCNQ1 coassembly in heterologous expression systems, several missense mutations in KCNE1 were identified in families affected by the long QT syndrome, which is associated with an increased risk of sudden cardiac death from torsades de pointes ventricular arrhythmias (10, 11). The QT interval is prolonged by hypokalemia (5), and observations similar to those in family members affected by the long QT syndrome were also made in KCNE1-deficient mice (7, 8, 13). These animals exhibit a prolonged QT interval, particularly during bradycardia, and are deaf. Both features are also typically observed in patients carrying homozygous KCNE1 mutations, convincingly demonstrating that KCNE1 plays a major role in the regulation of normal cardiac excitability and function of the inner ear.

Most interestingly, however, KCNE1-deficient mice reveal a number of additional abnormalities. They are hypokalemic; they lose large amounts of Na⁺ and K⁺ with their feces; they exhibit elevated plasma aldosterone levels; and they have a markedly increased fractional excretion of sodium chloride and fluid (1). The increased aldosterone levels can be seen, in part, as an attempt to compensate sodium loss as aldosterone correlates inversely with Na⁺ intake in the mouse (4). In addition, the regulation of aldosterone secretion from adrenal glomerulosa cells by plasma K⁺ is impaired in KCNE1-deficient mice (1). Taken together, these findings indicate a major physiological role of KCNE1 in K⁺ and fluid homeostasis. Even though the relevance of the noncardiac mouse phenotypes for the pathophysiology of the human long QT syndrome has yet to be defined, they may be of substantial clinical relevance, as hypokalemia is a well-known risk factor predisposing for torsades de pointes ventricular arrhythmias in humans. In addition to their possible clinical relevance, the findings in KCNE1-deficient mice summarized by Warth and Barhanin (14) demonstrate the power of physiological analysis of mice carrying targeted gene mutations to generate new insights into unexpected gene functions.

	FOOTNOTES

Address for reprint requests and other correspondence: H. Ehmke, Institut für Physiologie, Universität Hamburg, Martinistrasse 52, 20246 Hamburg, Germany (E-mail: ehmke{at}uke.uni-hamburg.de).

10.1152/ajpregu.00723.2001

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