Jeans Alexander F, Oliver Peter L, Johnson Reuben, Capogna Marco, Vikman Jenny, Molnár Zoltán, Babbs Arran, Partridge Christopher J, Salehi Albert, Bengtsson Martin, Eliasson Lena, Rorsman Patrik, Davies Kay E
Medical Research Council Functional Genetics Unit, University of Oxford, South Parks Road, Oxford, OX1 3QX, United Kingdom.
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2431-6. doi: 10.1073/pnas.0610222104. Epub 2007 Feb 5.
The neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential for synaptic vesicle exocytosis, but its study has been limited by the neonatal lethality of murine SNARE knockouts. Here, we describe a viable mouse line carrying a mutation in the b-isoform of neuronal SNARE synaptosomal-associated protein of 25 kDa (SNAP-25). The causative I67T missense mutation results in increased binding affinities within the SNARE complex, impaired exocytotic vesicle recycling and granule exocytosis in pancreatic beta-cells, and a reduction in the amplitude of evoked cortical excitatory postsynaptic potentials. The mice also display ataxia and impaired sensorimotor gating, a phenotype which has been associated with psychiatric disorders in humans. These studies therefore provide insights into the role of the SNARE complex in both diabetes and psychiatric disease.
神经元可溶性N - 乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）复合体对于突触小泡胞吐作用至关重要，但其研究一直受到小鼠SNARE基因敲除导致的新生期致死性限制。在此，我们描述了一种携带25 kDa神经元SNARE突触体相关蛋白（SNAP - 25）β异构体突变的存活小鼠品系。致病性I67T错义突变导致SNARE复合体内结合亲和力增加，胰腺β细胞中胞吐小泡再循环和颗粒胞吐受损，以及诱发的皮质兴奋性突触后电位幅度降低。这些小鼠还表现出共济失调和感觉运动门控受损，这种表型与人类精神疾病有关。因此，这些研究为SNARE复合体在糖尿病和精神疾病中的作用提供了见解。
