Published online before print October 25, 2001, doi: 10.1161/hh2301.100803
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Submitted on March 9, 2001
Revised on October 8, 2001
Accepted on October 16, 2001
Heteromultimeric Kv1.2-Kv1.5 Channels Underlie 4-Aminopyridine--Sensitive Delayed Rectifier K+ Current of Rabbit Vascular Myocytes
From The Smooth Muscle Research Group and Canadian Institutes for Health Research (CIHR) Group in Regulation of Vascular Contractility, University of Calgary, Alberta, Canada. Present address for O.C.-C. is Hoffmann-La-Roche Ltd, Preclinical Research, Basel, Switzerland; for K.I., the Department of Pharmacology, Yamagata University School of Medicine, Yamagata, Japan; and for D.P.S., the Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.
* To whom correspondence should be addressed. E-mail: wcole{at}ucalgary.ca.
The molecular identity of vascular delayed rectifier K+ channels (KDR) is poorly characterized. Inhibition by 4-aminopyridine (4-AP) of KDR of rabbit portal vein (RPV) myocytes was studied by patch clamp and compared with that of channels composed of Kv1.5 and/or Kv1.2 subunits cloned from the RPV and expressed in mammalian cells. 4-AP block of KDR was pulse-frequency dependent, required channel activation, and was associated with a positive shift in voltage dependence of activation. 4-AP caused a voltage-dependent reduction in mean open time of KDR. Relief of 4-AP block of whole cell currents during washout required channel activation and was unaffected by voltage. Homotetrameric Kv1.5 channels did not exhibit the shift in voltage dependence of activation exhibited by the native channels. In contrast, Kv1.2 channels displayed a shift in voltage dependence of activation, and this characteristic was also evident during 4-AP treatment when Kv1.2 was coexpressed with Kv1.5 or coupled to Kv1.5 in a tandem construct to produce heterotetrameric [Kv1.5/Kv1.2]2 channels. KDR currents were not sensitive to charybdotoxin, which blocks homotetrameric Kv1.2 channels. The findings of this study (1) indicate that vascular KDR are inhibited by 4-AP via an open-state block mechanism and trapping of the drug within the pore on channel closure and (2) provide novel evidence based on a comparison of functional characteristics that indicate the dominant form of vascular KDR channel complex in RPV involves the heteromultimeric association of Kv1.2 and Kv1.5 subunits.
Key words: vascular smooth muscle • KDR • 4-aminopyridine • Kv1.5 • Kv1.2 • voltage-gated K+ channel
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