Curia G, Aracri P, Sancini G, Mantegazza M, Avanzini G, Franceschetti S
Department of Neurophysiology, Laboratory of Experimental Epileptology, C. Besta National Neurological Institute, Via Celoria 11, 20133 Milan, Italy.
Neuroscience. 2004;127(1):63-8. doi: 10.1016/j.neuroscience.2004.04.040.
We investigated the interference of protein-kinase C (PKC)-dependent Na(+) channel phosphorylation on the inhibitory effect that the antiepileptic drug topiramate (TPM) has on persistent Na(+) currents (I(NaP)) by making whole cell patch-clamp and intracellular recordings of rat sensorimotor cortex neurons. The voltage-dependent activation of I(NaP) was significantly shifted in the hyperpolarizing direction when PKC was activated by 1-oleoyl-2-acetyl-sn-glycerol (OAG). TPM reduced the peak amplitude of I(NaP), but it did not counteract the OAG-induced shift in I(NaP) activation. Firing property experiments showed that the firing threshold was lowered by OAG. TPM was unable to counteract this effect, which may be due to OAG-dependent enhancement of the contribution of subthreshold I(NaP). These data suggest that PKC activation may limit the effect of the anticonvulsant TPM on the persistent fraction of Na(+) currents. The channel phosphorylation that may occur in cortical neurons as a result of physiological or pathological (e.g. epileptic) events can modulate the action of TPM on Na(+) currents.
我们通过对大鼠感觉运动皮层神经元进行全细胞膜片钳和细胞内记录，研究了蛋白激酶C（PKC）依赖性的Na⁺通道磷酸化对抗癫痫药物托吡酯（TPM）对持续性Na⁺电流（I(NaP)）抑制作用的干扰。当PKC被1-油酰基-2-乙酰基-sn-甘油（OAG）激活时，I(NaP)的电压依赖性激活在超极化方向上显著偏移。TPM降低了I(NaP)的峰值幅度，但它并未抵消OAG诱导的I(NaP)激活偏移。放电特性实验表明，OAG降低了放电阈值。TPM无法抵消这种效应，这可能是由于OAG依赖性增强了阈下I(NaP)的贡献。这些数据表明，PKC激活可能会限制抗惊厥药物TPM对Na⁺电流持续性部分的作用。由于生理或病理（如癫痫）事件可能在皮层神经元中发生的通道磷酸化，可以调节TPM对Na⁺电流的作用。
