Gazulla José, Tintoré Mari A
Department of Neurology, "Miguel Servet" University Hospital, Zaragoza, Spain.
Med Hypotheses. 2007;68(1):131-6. doi: 10.1016/j.mehy.2006.06.014. Epub 2006 Aug 8.
Voltage-dependent calcium channels (VDCCs) are heteromultimeric complexes that mediate calcium influx into cells in response to changes in membrane potential. The alpha1A subunit, encoded by the CACNA1A gene, is the pore-forming subunit specific to the neuronal P/Q-type VDCCs. These are implicated in fast excitatory and inhibitory neurotransmission. Their highest levels of expression are found in the Purkinje cell layer of the cerebellum, and in the hippocampus. Spinocerebellar ataxia type 6 (SCA 6) is an autosomal dominant cerebellar degeneration that shares neuropathological findings with late-onset cortical cerebellar atrophy (CCA). It is caused by an abnormal expansion of a trinucleotide (CAG) repeat in exon 47 of CACNA1A, on chromosome 19p13. This translates into a polyglutamine (polyQ) tract of prolonged length in the carboxyl terminal of the alpha1A subunit. Heterologous expression of mutated alpha1A subunits results in increased channel inactivation in electrophysiological tests. No treatment is known to improve SCA 6 at present, as none of the available drugs is able to reverse alpha1A dysregulation, nor disturbed protein aggregation, transport and localization in this disease. The drugs gabapentin and pregabalin interact with the alpha2delta subunit of the P/Q-type VDCCs. Gabapentin and pregabalin slow the rate of inactivation in recombinant P/Q-type VDCCs, expressed in Xenopus oocytes. These drugs improve ataxia in cases of CCA, olivopontocerebellar atrophy and ataxia-telangiectasia. On the basis of the neuropathological identity of SCA 6 with CCA, and given the capacity of gabapentin and pregabalin to decrease P/Q-type VDCCs inactivation, in this paper the authors put forward the hypothesis that the administration of gabapentin and pregabalin might prove beneficial in SCA 6 as the ataxia caused by this disease would be expected to improve. The authors hope that researchers working with this illness will be inspired and encouraged to undertake the appropriate clinical and experimental work.
电压依赖性钙通道（VDCCs）是异源多聚体复合物，可响应膜电位变化介导钙离子流入细胞。由CACNA1A基因编码的α1A亚基是神经元P/Q型VDCCs特有的孔形成亚基。这些通道与快速兴奋性和抑制性神经传递有关。它们在小脑的浦肯野细胞层和海马体中表达水平最高。6型脊髓小脑共济失调（SCA 6）是一种常染色体显性遗传性小脑变性疾病，与迟发性皮质小脑萎缩（CCA）具有相同的神经病理学表现。它是由位于19号染色体p13上的CACNA1A基因第47外显子中的三核苷酸（CAG）重复序列异常扩增引起的。这导致α1A亚基羧基末端的聚谷氨酰胺（polyQ）序列延长。在电生理测试中，突变的α1A亚基的异源表达导致通道失活增加。目前尚无已知的治疗方法可改善SCA 6，因为现有的药物均无法逆转α1A亚基的失调，也无法纠正该疾病中受干扰的蛋白质聚集、转运和定位。加巴喷丁和普瑞巴林这两种药物可与P/Q型VDCCs的α2δ亚基相互作用。加巴喷丁和普瑞巴林可减缓非洲爪蟾卵母细胞中表达的重组P/Q型VDCCs的失活速率。这些药物可改善CCA、橄榄桥脑小脑萎缩和共济失调毛细血管扩张症患者的共济失调症状。基于SCA 6与CCA在神经病理学上的一致性，以及加巴喷丁和普瑞巴林降低P/Q型VDCCs失活的能力，本文作者提出假说，即加巴喷丁和普瑞巴林的给药可能对SCA 6有益，因为预计该疾病引起的共济失调症状将会改善。作者希望研究该疾病的人员能受到启发并得到鼓励，开展适当的临床和实验工作。
