Department of Pharmacology, College of Physicians & Surgeons of Columbia University College, New York, New York 10032
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 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).
ARTICLE
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ARTICLE
REFERENCES
-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).
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FOOTNOTES |
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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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