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2 Yale University School of Medicine and West Haven Veterans Affairs Medical Center, New Haven, Connecticut 06510; and 1 University of Vermont, Burlington, Vermont 05446
Our laboratory previously cloned a novel rabbit gene
(Kcn1), expressed in kidney, heart, and aorta, and predicted to
encode a protein with 58% amino acid identity with the K channel
Shaker Kv1.3 (Yao X et al. Proc Natl Acad Sci USA 92:
11711-11715, 1995). Because Kcn1 did not express well
(peak current in Xenopus laevis oocytes of 0.3 µA at +60 mV),
the human homolog (KCNA10) was isolated, and its expression was
optimized in oocytes. KCNA10 mediates voltage-gated K+
currents that exhibit minimal steady-state inactivation. Ensemble currents of 5-10 µA at +40 mV were consistently recorded from injected oocytes. Channels are closed at the holding potential of
80 mV but are progressively activated by depolarizations more positive than 30 mV, with half-activation at +3.5 ± 2.5 mV.
The channel displays an unusual inhibitor profile because, in addition to being blocked by classical K channel blockers (barium
tetraethylammonium and 4-aminopyridine), it is also sensitive to
inhibitors of cyclic nucleotide-gated (CNG) cation channels (verapamil
and pimozide). Tail-current analysis shows a reversal potential shift
of 47 mV/decade change in K concentration, indicating a K-to-Na
selectivity ratio of at least 15:1. The phorbol ester phorbol
12-myristate 13-acetate, an activator of protein kinase C, inhibited
whole cell current by 42%. Analysis of single-channel
currents reveals a conductance of ~11 pS. We conclude KCNA10 is a
novel human voltage-gated K channel with features common to both
K-selective and CNG cation channels. Given its distribution in renal
blood vessels and heart, we speculate that KCNA10 may be involved in
regulating the tone of renal vascular smooth muscle and may also
participate in the cardiac action potential.
potassium channel; patch clamp; cyclic nucleotide voltage-gated; vasoregulation; Xenopus laevis oocyte; human
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