Ion fluxes in lysosomal membranes

溶酶体膜中的离子通量

• 批准号: 7324738
• 负责人: Joseph A Mindell
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7324738
• 关键词: Ion; fluxes; lysosomal; membranes

This was the first year for this project, which is using a combination of methods to analyze the ion transport properties of lysosomal membranes. Lysosomes are intracellular organelles that serve in most cells as digestive organelles although in some tissues they are used for other functions. Disorders of lysosome function lead to a variety of diseases including neurological dysfunction (lysosomal storage diseases) and osteopetrosis (overcalcification of bone). Lysosomes utilize an ATP-driven proton pump to maintain an acidic luminal pH and facilitate their digestive function. Such a pump can only be effective if accompanied by additional ion transport to dissipate the transmembrane voltage built up by the ATPase. Genetic evidence suggests that this additional ion pathway a ClC-type anion transporter, but functional experiments have not yet demonstrated such a pathway. We seek to identify the ion transport pathways in lysosomes, to characterize their properties, and to identify the responsible proteins. Our initial efforts have demonstrated the presence of a pH-dependent anion transport activity in lysosomal membranes, consistent with the presence of a functional ClC protein. In the upcoming year we will further characterize the functional properties of this transport and attempt to prove that it is mediated by a ClC transporter.

这是该项目的第一年，该项目使用多种方法来分析溶酶体膜的离子转运特性。溶酶体是细胞内的细胞器，在大多数细胞中充当消化细胞器，尽管在某些组织中它们用于其他功能。溶酶体功能障碍导致多种疾病，包括神经功能障碍（溶酶体贮积病）和骨硬化症（骨过度钙化）。溶酶体利用ATP驱动的质子泵来维持酸性的管腔pH值并促进其消化功能。这种泵只有在伴随额外的离子转运以耗散由ATP酶建立的跨膜电压时才有效。遗传学证据表明，这一额外的离子途径是ClC型阴离子转运蛋白，但功能实验尚未证明这样的途径。我们试图确定离子转运途径在溶酶体中，以表征其特性，并确定负责的蛋白质。我们最初的努力已经证明了在溶酶体膜中存在pH依赖性阴离子转运活性，这与功能性CLC蛋白的存在一致。在接下来的一年里，我们将进一步表征这种运输的功能特性，并试图证明它是由CLC转运蛋白介导的。