Podocin organizes ion channel-lipid supercomplexes: implications for mechanosensation at the slit diaphragm

Abstract

The slit diaphragm is part of a three-layered glomerular filter that prevents most proteins from entering the urinary space. As a highly specialized cell-cell contact the slit diaphragm has recently been appreciated as a signaling platform that regulates podocyte cell survival, polarity, endocytosis and cytoskeletal organization. Mutations in genes encoding slit diaphragm proteins contribute to human hereditary glomerular diseases. Recently, it was discovered that transient receptor potential ion channel TRPC6 mutations cause familial glomerular disease. TRPC6 localizes to the slit diaphragm unexpectedly adding an ion channel to the list of signaling molecules functioning at this complex structure. Recent findings highlight a potential role for TRPC6 at the filtration barrier. TRPC6 has been identified as a sensor of mechanically and osmotically induced membrane stretch. In the context of the slit diaphragm signaling network, TRPC6 is clustered and regulated by a podocin-lipid complex that might translate mechanical tension to ion channel action. This review will summarize the most recent findings on protein-lipid supercomplexes at the slit diaphragm and discuss a potential novel function of the slit diaphragm as a mechanosensor.