Heteromultimeric Kv1.2-Kv1.5 Channels Underlie 4-Aminopyridine-Sensitive Delayed Rectifier K+ Current of Rabbit Vascular Myocytes

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 an...

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Bibliographic Details
Published in:Circulation research 2001-11, Vol.89 (11), p.1038-1044
Main Authors: Kerr, Paul M, Clément-Chomienne, Odile, Thorneloe, Kevin S, Chen, Tim T, Ishii, Kuniaki, Sontag, David P, Walsh, Michael P, Cole, William C
Format: Article
Language:English
Subjects:
4-Aminopyridine - metabolism
4-Aminopyridine - pharmacology
Animals
Biological and medical sciences
Blood vessels and receptors
Cells, Cultured
Charybdotoxin - pharmacology
Delayed Rectifier Potassium Channels
Electric Conductivity
Fundamental and applied biological sciences. Psychology
Kinetics
Kv1.2 Potassium Channel
Kv1.5 Potassium Channel
Muscle, Smooth, Vascular - physiology
Patch-Clamp Techniques
Portal Vein - cytology
Potassium Channel Blockers - metabolism
Potassium Channel Blockers - pharmacology
Potassium Channels - chemistry
Potassium Channels - genetics
Potassium Channels - physiology
Potassium Channels, Voltage-Gated
Protein Subunits
Rabbits
Transfection
Vertebrates: cardiovascular system
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Summary: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.
ISSN:0009-7330
1524-4571
DOI:10.1161/hh2301.100803