Etxeberria Ainhoa, Aivar Paloma, Rodriguez-Alfaro Jose Angel, Alaimo Alessandro, Villacé Patricia, Gómez-Posada Juan Camilo, Areso Pilar, Villarroel Alvaro
Unidad de Biofísica, CSIC-UPV/EHU, Universidad del País Vasco, Barrio Sarriena s/n, 48940 Leioa, Spain.
FASEB J. 2008 Apr;22(4):1135-43. doi: 10.1096/fj.07-9712com. Epub 2007 Nov 9.
Voltage-dependent potassium KCNQ2 (Kv7.2) channels play a prominent role in the control of neuronal excitability. These channels must associate with calmodulin to function correctly and, indeed, a mutation (R353G) that impairs this association provokes the onset of a form of human neonatal epilepsy known as benign familial neonatal convulsions (BFNC). We show here that perturbation of calmodulin binding leads to endoplasmic reticulum (ER) retention of KCNQ2, reducing the number of channels that reach the plasma membrane. Interestingly, elevating the expression of calmodulin in the BFNC mutant partially restores the intracellular distribution of the KCNQ channel. In contrast, overexpression of a Ca(2+)-binding incompetent calmodulin or sequestering of calmodulin promotes the retention of wild-type channels in the ER. Thus, a direct interaction with Ca(2+)-calmodulin appears to be critical for the correct activity of KCNQ2 potassium channels as it controls the channels' exit from the ER.
电压依赖性钾离子通道KCNQ2（Kv7.2）在控制神经元兴奋性方面发挥着重要作用。这些通道必须与钙调蛋白结合才能正常发挥功能，事实上，一种损害这种结合的突变（R353G）会引发一种称为良性家族性新生儿惊厥（BFNC）的人类新生儿癫痫。我们在此表明，钙调蛋白结合的扰动会导致KCNQ2在内质网（ER）中滞留，减少到达质膜的通道数量。有趣的是，提高BFNC突变体中钙调蛋白的表达可部分恢复KCNQ通道的细胞内分布。相反，过表达不能结合Ca(2+)的钙调蛋白或螯合钙调蛋白会促进野生型通道在内质网中的滞留。因此，与Ca(2+)-钙调蛋白的直接相互作用似乎对KCNQ2钾通道的正确活性至关重要，因为它控制着通道从内质网的输出。
