Inhibition of voltage‐dependent sodium channels by Ro 31‐8220, a ‘specific’ protein kinase C inhibitor

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 [3H]batrachotoxinin‐A 20‐α‐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.

[1]  S. Coultrap,et al.  Competitive antagonism of the mouse 5-hydroxytryptamine3 receptor by bisindolylmaleimide I, a "selective" protein kinase C inhibitor. , 1999, The Journal of pharmacology and experimental therapeutics.

[2]  D. Nicholls,et al.  Protein kinase C modulates field‐evoked transmitter release from cultured rat cerebellar granule cells via a dendrotoxin‐sensitive K+ channel , 1999, The European journal of neuroscience.

[3]  B. Scott,et al.  Electric membrane properties of adult mouse DRG neurons and the effect of culture duration. , 1980, Journal of neurobiology.

[4]  J. Rostas,et al.  A rapid method for isolation of synaptosomes on Percoll gradients , 1986, Brain Research.

[5]  P. Marley,et al.  Inhibition of nicotinic responses of bovine adrenal chromaffin cells by the protein kinase C inhibitor, Ro 31–8220 , 1996, British journal of pharmacology.

[6]  D. Nicholls,et al.  Protein kinase C and the regulation of glutamate exocytosis from cerebrocortical synaptosomes. , 1993, The Journal of biological chemistry.

[7]  T. Hunter,et al.  The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. , 1988, Science.

[8]  P. Davis,et al.  Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity. , 1992, Journal of medicinal chemistry.

[9]  J. Tavaré,et al.  The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31‐8220) are potent inhibitors of glycogen synthase kinase‐3 activity , 1999, FEBS letters.

[10]  D. Nicholls,et al.  The glutamatergic nerve terminal. , 1993, European journal of biochemistry.

[11]  D. Alessi.  The protein kinase C inhibitors Ro 318220 and GF 109203X are equally potent inhibitors of MAPKAP kinase‐1β (Rsk‐2) and p70 S6 kinase , 1997, FEBS letters.

[12]  L. Ratnakumari,et al.  Inhibition by propofol of [3H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes , 1996, British journal of pharmacology.

[13]  S. Lazareno,et al.  Muscarinic interactions of bisindolylmaleimide analogues. , 1998, European journal of pharmacology.

[14]  H. Coste,et al.  The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. , 1991, The Journal of biological chemistry.

[15]  D. Nicholls,et al.  Calcium‐Dependent and‐Independent Release of Glutamate from Synaptosomes Monitored by Continuous Fluorometry , 1987, Journal of neurochemistry.

[16]  P. G. Kostyuk,et al.  Ionic currents in the somatic membrane of rat dorsal root ganglion neurons—I. Sodium currents , 1981, Neuroscience.

[17]  L. Ratnakumari,et al.  Effects of Propofol on Sodium Channel‐dependent Sodium Influx and Glutamate Release in Rat Cerebrocortical Synaptosomes , 1997, Anesthesiology.

[18]  P. Parker,et al.  Isoenzyme specificity of bisindolylmaleimides, selective inhibitors of protein kinase C. , 1993, The Biochemical journal.

[19]  Ming Li,et al.  Convergent regulation of sodium channels by protein kinase C and cAMP-dependent protein kinase. , 1993, Science.

[20]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.