Synaptic PI(3,4,5)P₃ Is Required for Syntaxin1A Clustering and Neurotransmitter Release

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• 作者：Thang Manh Khuong¹ ; ² ; Ron L.P. Habets¹ ; ² ; ⁵ ; Sabine Kuenen¹ ; ² ; Agata Witkowska⁴ ; Jaroslaw Kasprowicz¹ ; ² ; Jef Swerts¹ ; ² ; Reinhard Jahn⁴ ; Geert van den Bogaart³ ; ⁴ ; Patrik Verstreken¹ ; ² ; ^{patrik.verstreken@cme.vib-kuleuven.be}
• 刊名：Neuron
• 出版年：2013
• 出版时间：20 March, 2013
• 年：2013
• 卷：77
• 期：6
• 页码：1097-1108
• 全文大小：1618 K

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Summary

PI(3,4,5)P₃ is a low-abundance lipid thought to play?a?role in the regulation of synaptic activity; however, the mechanism remains obscure. We have constructed novel split Venus-based probes and used superresolution imaging to localize PI(3,4,5)P₃ at Drosophila larval neuromuscular synapses. We find the lipid in membrane domains at neurotransmitter release sites, where it concentrates with Syntaxin1A, a protein essential for vesicle fusion. Reducing PI(3,4,5)P₃ availability disperses Syntaxin1A clusters and increasing PI(3,4,5)P₃ levels rescues this defect. In artificial giant unilamellar vesicles, PI(3,4,5)P₃ also?induces Syntaxin1A domain formation and this clustering, in?vitro and in?vivo, is dependent on positively charged residues in the Syntaxin1A-juxtamembrane domain. Functionally, reduced PI(3,4,5)P₃ causes temperature-sensitive paralysis and reduced neurotransmitter release, a phenotype also seen in animals expressing a Syntaxin1A with a mutated juxtamembrane domain. Thus, our data indicate that PI(3,4,5)P₃, based on electrostatic interactions, clusters Syntaxin1A at release sites to regulate neurotransmitter release.