Capendeguy Oihana, Horisberger Jean-Daniel
Department of Pharmacology and Toxicology, Université de Lausanne, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland.
Neuromolecular Med. 2004;6(2-3):105-16. doi: 10.1385/NMM:6:2-3:105.
Familial hemiplegic migraine type 2, an autosomal dominant form of migraine with aura, has been associated with four distinct mutations in the alpha2-subunit of the Na+,K+-ATPase. We have introduced these mutations in the alpha2-subunit of the human Na+,K+-ATPase and the corresponding mutations in the Bufo marinus alpha1-subunit and studied these mutants by expression in Xenopus oocyte. Metabolic labeling studies showed that the mutants were synthesized and associated with the beta-subunit, except for the alpha2HW887R mutant, which was poorly synthesized, and the alpha1BW890R, which was partially retained in the endoplasmic reticulum. [3H]ouabain binding showed the presence of the alpha2HR689Q and alpha2HM731T at the membrane, whereas the alpha2HL764P and alpha2HW887R could not be detected. Functional studies with the mutants of the B. marinus Na+,K+-ATPase showed a reduced or abolished electrogenic activity and a low K+ affinity for the alpha1BW890R mutant. Through different mechanisms, all these mutations result in a strong decrease of the functional expression of the Na+,K+-pump. The decreased activity in alpha2 isoform of the Na+,K+-pump expressed in astrocytes seems an essential component of hemiplegic migraine pathogenesis and may be responsible for the cortical spreading depression, which is one of the first events in migraine attacks.
家族性偏瘫型偏头痛2型是偏头痛伴先兆的常染色体显性遗传形式，与Na⁺,K⁺-ATP酶α2亚基的四种不同突变有关。我们已将这些突变引入人Na⁺,K⁺-ATP酶的α2亚基以及海蟾蜍α1亚基的相应突变中，并通过在非洲爪蟾卵母细胞中表达来研究这些突变体。代谢标记研究表明，除了合成较差的α2HW887R突变体和部分保留在内质网中的α1BW890R突变体外，其他突变体均能合成并与β亚基结合。[³H]哇巴因结合显示α2HR689Q和α2HM731T存在于细胞膜上，而α2HL764P和α2HW887R无法检测到。对海蟾蜍Na⁺,K⁺-ATP酶突变体的功能研究表明，α1BW890R突变体的电生活动降低或消失，且对K⁺的亲和力较低。通过不同机制，所有这些突变都会导致Na⁺,K⁺泵的功能表达大幅下降。在星形胶质细胞中表达的Na⁺,K⁺泵α2同工型活性降低似乎是偏瘫型偏头痛发病机制的一个重要组成部分，可能是偏头痛发作早期事件之一——皮层扩散性抑制的原因。
