Abstract
We find that several protein kinase C (PKC) inhibitors, previously considered to be specific, directly inhibit voltage-dependent Na(+) channels at their useful concentrations. Bisindolylmaleimide I (GF 1092037), IX (Ro 31-8220) and V (an inactive analogue), but not H7 (a non-selective isoquinolinesulfonamide protein kinase inhibitor), inhibited Na(+) channels assessed by several independent criteria: Na(+) channel-dependent glutamate release and [(3)H]batrachotoxinin-A 20-alpha-benzoate binding in rat cortical synaptosomes, veratridine-stimulated 22Na(+) influx in CHO cells expressing rat CNaIIa Na(+) channels and Na(+) currents measured in isolated rat dorsal root ganglion neurons by whole cell patch-clamp recording. These findings limit the usefulness of the bisindolylmaleimide class PKC inhibitors in excitable cells.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Binding, Competitive
-
CHO Cells
-
Cerebral Cortex / drug effects
-
Cerebral Cortex / metabolism
-
Cricetinae
-
Dose-Response Relationship, Drug
-
Enzyme Inhibitors / pharmacology*
-
Ganglia, Spinal / cytology
-
Ganglia, Spinal / drug effects
-
Ganglia, Spinal / physiology
-
Glutamic Acid / drug effects
-
Glutamic Acid / metabolism
-
Indoles / pharmacology*
-
Maleimides / pharmacology
-
Membrane Potentials / drug effects
-
Neurons / drug effects
-
Neurons / physiology
-
Patch-Clamp Techniques
-
Protein Kinase C / antagonists & inhibitors*
-
Rats
-
Rats, Sprague-Dawley
-
Sodium Channel Blockers*
-
Synaptosomes / drug effects
-
Synaptosomes / metabolism
-
Veratridine / pharmacology
Substances
-
Enzyme Inhibitors
-
Indoles
-
Maleimides
-
Sodium Channel Blockers
-
Glutamic Acid
-
Veratridine
-
Protein Kinase C
-
bisindolylmaleimide I
-
Ro 31-8220