Roscovitine differentially affects CaV2 and Kv channels by binding to the open state

• Published in: Neuropharmacology Vol. 52; no. 3; pp. 883 - 894
• Main Authors: Buraei, Zafir, Schofield, Geoffrey, Elmslie, Keith S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2007
• Subjects: Bullfrog sympathetic neurons; Calcium Channels, L-Type - physiology; CaV cell lines; CaV2 enhancement; Caveolin 2 - physiology; Cell Line, Transformed; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Electric Stimulation - methods; Humans; Ion Channel Gating - drug effects; Kv inhibition; Membrane Potentials - drug effects; Membrane Potentials - genetics; Membrane Potentials - radiation effects; Open channel; Patch-Clamp Techniques - methods; Protein Kinase Inhibitors - pharmacology; Purines - pharmacology; Transfection - methods; Whole-cell patch clamp; CaV cell lines; Bullfrog sympathetic neurons; CaV2 enhancement; Kv inhibition; Whole-cell patch clamp; Open channel
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2006.10.006

Roscovitine potently inhibits cyclin-dependent kinases (CDK) and can independently slow the closing of neuronal (CaV2.2) calcium channels. We were interested if this drug could affect other ion channels similarly. Using whole cell recordings, we found that roscovitine specifically slows deactivation of all CaV2 channels (N, P/Q and R) by binding to the open state. This effect had a rapid onset and EC 50 = 54, 120 and 54 μM for N-, P/Q-, and R-type channels, respectively. Deactivation of other channel types was not slowed, including L-type calcium channels (CaV1.2, CaV1.3), potassium channels (native, Kv4.2, Kv2.1 and Kv1.3), and native sodium channels. However, most of the channels tested were inhibited by roscovitine. The inhibition was characterized by slow development and a lower affinity (EC 50 = 100–300 μM). Surprisingly, potassium channels were rapidly inhibited with an EC 50 = 23 μM, which is similar to the EC 50 for roscovitine block of cell division [Meijer, L., Borgne, A., Mulner, O., Chong, J., Blow, J., Inagaki, N., Inagaki, M., Delcros, J., Moulinoux, J., 1997. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 243, 527–536]. Potassium current inhibition seemed to result from open channel block. The high potency of these two rapid onset effects makes them complicating factors for ongoing clinical trials and research using roscovitine. Thus, the physiology and pharmacology of slow CaV2 deactivation and potassium channel block must be explored.