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Volume 272, Number 50, Issue of December 12, 1997
pp. 31598-31603
(Received for publication, July 7, 1997, and in revised form, August 28, 1997)
From the Section of Molecular and Cellular Cardiology and the
To probe the molecular identity of transient
outward (A-type) potassium currents, we expressed a truncated version
of Kv4.2 in heart cells and neurons. The rat Kv4.2-coding sequence was truncated at a position just past the first transmembrane segment and
subcloned into an adenoviral shuttle vector downstream of a
cytomegalovirus promoter (pE1Kv4.2ST). We hypothesized that this
construct would act as a dominant-negative suppressor of currents
encoded by the Kv4 family by analogy to Kv1 channels. Cotransfection of
wild-type Kv4.2 with a
Suppression of Neuronal and Cardiac Transient Outward Currents by
Viral Gene Transfer of Dominant-Negative Kv4.2 Constructs
,
Graduate Program in Cellular and Molecular Medicine, The
Johns Hopkins University, Baltimore, Maryland 21205
-galactosidase expression vector in Chinese
hamster ovary (CHO)-K1 cells produced robust transient outward currents
(Ito) after two days (14.0 pA/pF at 50 mV,
n = 5). Cotransfection with pE1Kv4.2ST markedly
suppressed the Kv4.2 currents (0.8 pA/pF, n = 6, p < 0.02; cDNA ratio of 2:1 Kv4.2ST:wild type),
but in parallel experiments, it did not alter the current density of
coexpressed Kv1.4 or Kv1.5 channels. Kv4.2ST also effectively
suppressed rat Kv4.3 current when coexpressed in CHO-K1 cells. We then
engineered a recombinant adenovirus (AdKv4.2ST) designed to overexpress
Kv4.2ST in infected cells. A-type currents in rat cerebellar granule
cells were decreased two days after AdKv4.2ST infection as compared
with those infected by a -galactosidase reporter virus (116.0 pA/pF
versus 281.4 pA/pF in Ad -galactosidase cells,
n = 8 each group, p < 0.001).
Likewise, Ito in adult rat ventricular myocytes was
suppressed by AdKv4.2ST but not by Ad-galactosidase (8.8 pA/pF
versus 21.4 pA/pF in -galactosidase cells,
n = 6 each group, p < 0.05).
Expression of a GFP-Kv4.2ST fusion construct enabled imaging of
subcellular protein localization by confocal microscopy. The protein
was distributed throughout the surface membrane and intracellular
membrane systems. We conclude that genes from the Kv4 family are the
predominant contributors to the A-type currents in cerebellar granule
cells and Ito in rat ventricle. Overexpression of
dominant-negative constructs may be of general utility in dissecting
the contributions of various ion channel genes to excitability.
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