PT  - JOURNAL ARTICLE
AU  - Jonathan Ledoux
AU  - Denis Chartier
AU  - Normand Leblanc
TI  - Inhibitors of Calmodulin-Dependent Protein Kinase Are Nonspecific Blockers of Voltage-Dependent K<sup>+</sup> Channels in Vascular Myocytes
DP  - 1999 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1165--1174
VI  - 290
IP  - 3
4099  - http://jpet.aspetjournals.org/content/290/3/1165.short
4100  - http://jpet.aspetjournals.org/content/290/3/1165.full
SO  - J Pharmacol Exp Ther1999 Sep 01; 290
AB  - The present study was undertaken to investigate the effects of specific inhibitors of calmodulin-dependent protein kinase II (CamKII) on macroscopic voltage-dependent K+ current (KV) recorded from rabbit portal vein smooth muscle cells. Inhibition of L-type Ca2+ current facilitation by 1 μM KN-62, a blocker of CamKII, was first demonstrated and provided evidence for functional CamKII activity in this preparation. KN-93, another specific and more potent inhibitor of CamKII in the rat brain, suppressed KVand enhanced the rate of inactivation in a dose-dependent manner, in cells dialyzed with both low (0.1 mM) and high (10 mM) EGTA pipette solution. Prolonged dialysis with 10 μM of a synthetic peptide inhibitor of CamKII (fragment 281–301) had little effect on KV and did not prevent the inhibitory action of KN-93 on the current. The estimated IC50 for inhibiting peak and late currents during 250-ms steps to +60 mV (holding potential = −60 mV) were 2.9 and 0.27 μM, respectively. KN-93 also induced slight shifts of the steady-state activation (−7 mV) and inactivation (−6 mV) curves. KN-62, and KN-92, an inactive analog of KN-93, produced effects similar to those of KN-93. In current clamp experiments, 5 μM KN-93 depolarized the myocytes from a control resting membrane potential of −42.3 ± 2.8 mV to −28.5 ± 1.4 mV, an effect that was partially reversible after washout (−34.4 ± 1.3 mV, n = 6). In conclusion, blockers of CamKII produce nonspecific inhibitory effects on KV that warrant cautious use of these compounds in physiological experiments designed to assess the role of CamKII. The American Society for Pharmacology and Experimental Therapeutics