CaMKII-independent effects of KN93 and its inactive analog KN92: reversible inhibition of L-type calcium channels

Biochem Biophys Res Commun. 2006 Jul 14;345(4):1606-10. doi: 10.1016/j.bbrc.2006.05.066. Epub 2006 May 19.


Widely regarded as a specific and potent inhibitor of CaM kinases, especially CaMKII, KN93 has long been used to investigate the possible roles of CaMKII in a wide range of biological functions and systems, such as cultured cells, primary neurons, and brain slices. However, here we present evidence showing that KN93 and its structural analog KN92, which does not inhibit CaMKII, exert an unexpected, reversible, and specific reduction of currents of L-type calcium channels (CaV1.3 and CaV1.2), as compared to N-type calcium channels (CaV2.2). This effect is dependent not only on incubation time, but also on the dose of KN93 or KN92. Moreover, the effect appears to be independent of endocytosis, exocytosis, and proteasome activity. Washout and return to normal media rescues the L channel currents. Conversely, the structurally unrelated CaMKII inhibitor, AIP, fails to mimic the KN93/KN92 effect on L channel currents. Together, our data suggest that, in addition to inhibiting CaMKII, KN93 also affects CaV1.3 and CaV1.2 calcium channels in a CaMKII-independent manner.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Benzylamines / pharmacology*
  • Brefeldin A / pharmacology
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / physiology*
  • Calcium Channels, N-Type / genetics
  • Calcium Channels, N-Type / physiology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Humans
  • Leupeptins / pharmacology
  • Macrolides / pharmacology
  • Membrane Potentials / drug effects
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Sulfonamides / pharmacology*
  • Time Factors
  • Transfection


  • Benzylamines
  • CACNA1B protein, human
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Calcium Channels, N-Type
  • KN 92
  • L-type calcium channel alpha(1C)
  • Leupeptins
  • Macrolides
  • Protein Kinase Inhibitors
  • Sulfonamides
  • alpha1D (Cav1.3) L-type calcium channel, human
  • KN 93
  • Brefeldin A
  • bafilomycin A1
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde