Uchitel Osvaldo D, González Inchauspe Carlota, Di Guilmi Mariano N
Instituto de Fisiología, Biología Molecular y Neurociencias (CONICET), Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, piso 2, Ciudad Universitaria, Buenos Aires, 1428, Argentina.
Biophys Rev. 2014 Mar;6(1):15-26. doi: 10.1007/s12551-013-0126-y. Epub 2013 Dec 3.
One of the outstanding developments in clinical neurology has been the identification of ion channel mutations as the origin of a wide variety of inherited disorders like migraine, epilepsy, and ataxia. The study of several channelopathies has provided crucial insights into the molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological diseases. This review addresses the mutations underlying familial hemiplegic migraine (FHM) with particular interest in Cav2.1 (i.e., P/Q-type) voltage-activated Ca channel FHM type-1 mutations (FHM1). Transgenic mice harboring the human pathogenic FHM1 mutation R192Q or S218L (KI) have been used as models to study neurotransmission at several central and peripheral synapses. FHM1 KI mice are a powerful tool to explore presynaptic regulation associated with expression of Cav2.1 channels. FHM1 Cav2.1 channels activate at more hyperpolarizing potentials and show an increased open probability. These biophysical alterations may lead to a gain-of-function on synaptic transmission depending upon factors such as action potential waveform and/or Cav2.1 splice variants and auxiliary subunits. Analysis of FHM knock-in mouse models has demonstrated a deficient regulation of the cortical excitation/inhibition (E/I) balance. The resulting excessive increases in cortical excitation may be the mechanisms that underlie abnormal sensory processing together with an increase in the susceptibility to cortical spreading depression (CSD). Increasing evidence from FHM KI animal studies support the idea that CSD, the underlying mechanism of aura, can activate trigeminal nociception, and thus trigger the headache mechanisms.
临床神经学的一项杰出进展是，已确定离子通道突变是偏头痛、癫痫和共济失调等多种遗传性疾病的病因。对几种离子通道病的研究为复杂神经系统疾病的分子机制、发病机制和治疗方法提供了关键见解。本综述探讨家族性偏瘫性偏头痛（FHM）的潜在突变，尤其关注Cav2.1（即P/Q型）电压门控钙通道FHM1型突变（FHM1）。携带人类致病性FHM1突变R192Q或S218L（KI）的转基因小鼠已被用作模型，以研究多个中枢和外周突触的神经传递。FHM1 KI小鼠是探索与Cav2.1通道表达相关的突触前调节的有力工具。FHM1 Cav2.1通道在更超极化的电位下激活，并显示出开放概率增加。这些生物物理改变可能导致突触传递功能增强，这取决于动作电位波形和/或Cav2.1剪接变体及辅助亚基等因素。对FHM基因敲入小鼠模型的分析表明，皮质兴奋/抑制（E/I）平衡调节不足。由此导致的皮质兴奋过度增加可能是异常感觉处理的机制，同时也是皮质扩散性抑制（CSD）易感性增加的机制。来自FHM KI动物研究的越来越多的证据支持这样一种观点，即CSD作为先兆的潜在机制，可以激活三叉神经痛觉，从而触发头痛机制。
