title: PI(4,5)P₂-binding effector proteins for vesicle exocytosis.
abstract: PI(4,5)P₂participates directly in priming and possibly in fusion steps of Ca²⁺-triggered vesicle exocytosis. High concentration nanodomains of PI(4,5)P₂reside on the plasma membrane of neuroendocrine cells. A subset of vesicles that co-localize with PI(4,5)P₂ domains appear to undergo preferential exocytosis in stimulated cells. PI(4,5)P₂directly regulates vesicle exocytosis by recruiting and activating PI(4,5)P₂-binding proteins that regulate SNARE protein function including CAPS, Munc13-1/2, synaptotagmin-1, and other C2 domain-containing proteins. These PI(4,5)P₂effector proteins are coincidence detectors that engage in multiple interactions at vesicle exocytic sites. The SNARE protein syntaxin-1 also binds to PI(4,5)P₂, which promotes clustering, but an activating role for PI(4,5)P₂in syntaxin-1 function remains to be fully characterized. Similar principles underlie polarized constitutive vesicle fusion mediated in part by the PI(4,5)P₂-binding subunits of the exocyst complex (Sec3, Exo70). Overall, focal vesicle exocytosis occurs at sites landmarked by PI(4,5)P2, which serves to recruit and/or activate multifunctional PI(4,5)P₂-binding proteins. This article is part of a Special Issue entitled Phosphoinositides.
authors.affiliation: Biochemistry Department, University of Wisconsin, 433 Babcock Drive, Madison, WI 53706, USA. Electronic address: tfmartin@wisc.edu.
authors.forename: Thomas F J
authors.initials: TF
authors.lastname: Martin
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005089:Exocytosis / Q000235:genetics*; D005786:Gene Expression Regulation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D050863:Synaptotagmin I / Q000235:genetics / Q000378:metabolism; D050827:Syntaxin 1 / Q000235:genetics / Q000378:metabolism; D022161:Transport Vesicles / Q000737:chemistry / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D050863:Synaptotagmin I; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins; D002118:Calcium
keywords: CAPS/CADPS; Munc13; Phosphatidylinositol(4,5)bisphosphate; SNARE protein; Synaptotagmin; Vesicle exocytosis