EDITORIAL FOCUS
KChAP: a novel chaperone for specific K+ channels key to repolarization of the cardiac action potential. Focus on "KChAP as a chaperone for specific K+ channels"

H. Abriel, H. Motoike, and R. S. Kass

Department of Pharmacology, College of Physicians & Surgeons of Columbia University College, New York, New York 10032


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THE BIOSYNTHESIS OF ION CHANNELS is complex, and its tight regulation occurs at different levels, i.e., gene expression, transcription, as well as pre- and posttranscriptional processing (7). During the last 10 years, emphasis has focused primarily on subunit organization of ion channels, their regulation that is mediated by second messengers such as cAMP (22), and membrane targeting and subunit assembly (10, 12, 13, 18). Despite significant advances in these areas, we still know very little about the basic mechanisms involved in the membrane turnover of ion channels. In the current article in focus (Ref. 16, see page C931 in this issue), Kuryshev and co-workers have shed some light on the involvement of KChAP, a molecular chaperone for K+ channels in the regulation of functional K+ channels (19).

KChAP was recently cloned as a cytoplasmic protein that binds to Kv channels, using the yeast two-hybrid system (19), and has been found to belong to a family of transcription factor binding proteins. When coexpressed in cells, KChAP enhances the expression of specific K+ channels. Although still not understood in detail, the mechanism by which this effect is obtained has no precedent in the field. It seems that KChAP must be expressed closely to the Kv channel protein, but it is not found in the cell membrane, suggesting that KChAP plays a key role in channel biosynthesis. The experiments described in this study combine an elegant use of molecular biology with imaging and electrophysiological techniques. These new findings define KChAP as a unique class of ion channel modulators that are distinct from auxiliary subunits of ion channels with chaperone-like function, for example, the 1-transmembrane domain protein family, i.e., MinK, MiRP1, and the beta -subunits of the P-ATPases (1, 6, 14). In these instances, the auxiliary subunits are required for the complete function of the channel protein. Coexpression of KChAP does not influence the biophysical parameters of Kv channels but instead enhances total current density, suggesting a true chaperone function. Similar trafficking signaling regulates subunit stoichiometry of membrane K(ATP) channels and hence their functional expression (21).

The physiological relevance of this newly described regulatory mechanism is reflected by the specificity of KChAP to certain cardiac isoforms of Kv channels. One Kv channel isoform (Kv.4.3) produces the transient outward current (Ito) and is known to be differentially expressed in various regions of the heart (8, 9, 20), with significant functional consequences for the timing of ventricular repolarization (3-5, 17). It will be of great interest to determine what roles, if any, KChAP plays in directing these channels to their proper destination. Dysfunctional assembly and turnover can contribute to abnormal electrical impulse propagation in excitable tissues, and hence inherited mutations in KChAPs may add yet one more possible molecular and genetic factor that must be taken into account when investigating the mutational basis of inherited arrhythmias in the heart (15), as has been recently reported by Furutani et al. (11).

The report by Kuryshev and co-workers clearly demonstrates a role of a K+ channel specific chaperone in the assembly of functional channel proteins and adds critical insight into molecular steps in this process. This work now invites further investigation into putative roles of KChAP in regulating expression of Kv4.3 protein regionally in the heart, and in dysfunctional regulation of Kv4.3 protein expression in diseases such as Brugada's syndrome, where it is thought that regional differences in Ito expression play a key role in the disease phenotype (2, 5).


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Address for reprint requests and other correspondence: R. S. Kass, Dept. of Pharmacology, College of Physicians & Surgeons of Columbia Univ. College, 630 W. 168th St., New York, NY 10032 (E-mail: rsk20{at}columbia.edu).


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Am J Physiol Cell Physiol 278(5):C863-C864
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