Differences in the sensitivity of the TTX-resistant Na⁺ channel to the PKCβ inhibitor LY333531 in small dorsal root ganglion neurons of control and diabetic rats

Abstract

Experimental evidence has been presented to suggest that the protein kinase Cβ inhibitor LY333531 is effective at alleviating diabetic hyperalgesia to some extent. The present study was designed to examine the acute action of LY333531 (0.01-1μM) on the tetrodotoxin (TTX)-resistant Na⁺ current (I_Na) in small (<25 mm in soma diameter) dorsal root ganglion (DRG) neurons in control and streptozocin (STZ)-induced diabetic rats, using the whole-cell patch-clamp method. The cell membrane was initially hyperpolarized from a holding potential of -70 mV to -120 mV for 20 ms and then depolarized to various test potentials ranging from -50 to +50 mV, in the presence of TTX (0.1 mM) and the appropriate blockers for Ca²⁺ and K⁺ currents. I_Na was measured as a transient inward current during depolarizing steps. The maximal density of I_Na was significantly increased in diabetic rats compared with control (50.5 pApF⁻¹ vs 32.3 ⁻¹). I_Na recorded from diabetic rats was found to exhibit a significantly higher sensitivity to inhibition by LY333531 compared with control (IC₅₀, 6 nM vs 30 nM). Thus, our results provide experimental evidence to show that the sensitivity of I_Na to LY333531 is substantially enhanced by diabetic state, which suggests that I_Na is considerably inhibited by LY333531 at clinically relevant concentrations of <100 nM in diabetic state. [J Physiol Sci. 2006;56 Suppl:S149]