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Cited by 124Cellular transport and secretionExtracellular vesicles in diseaseProtein Kinase Regulation and GTPase Signaling

PI(4,5)P2-binding effector proteins for vesicle exocytosis

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Martin, Thomas F.J.·2015·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
DOI 10.1016/j.bbalip.2014.09.017PMC PMC4380529
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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.

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  • PI(4,5)P2 participates in multiple aspects of exocytosis including docking, priming and fusion of secretory granules.

    “Thus PI(4,5)P2 participates in multiple aspects of exocytosis including docking, priming and fusion of secretory granules [111].”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [111]

    The Introduction states that PI(4,5)P2 has an essential role in vesicle priming, and the Abstract says it possibly participates in fusion. Section 2 reports PI(4,5)P2 domains at a subset of docked dense-core vesicles, but does not establish that PI(4,5)P2 participates in docking itself. The claim also omits the paper’s uncertainty about its role in fusion. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • PI(4,5)P2 clusters in the cytoplasmic leaflet align with cholesterol- and sphingomyelin-rich regions in the external leaflet by trans-bilayer coupling.

    “Basically, current studies strongly suggest that PI(4,5)P2 clusters in the cytoplasmic leaflet align with cholesterol- and sphingomyelin-rich regions in the external leaflet of the plasma membranes by a mechanism referred to as trans-bilayer coupling [111,127–130].”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [111]

    Section 3 reports evidence that inner-leaflet PI(4,5)P2 clusters align with cholesterol- and sphingomyelin-rich outer-leaflet regions, but qualifies this as occurring at least at some plasma-membrane sites. It calls the basis of cluster formation unresolved and does not establish trans-bilayer coupling as the mechanism. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Martin, T. F. J.
Affiliations
University of Wisconsin System (US)
Corresponding author
Martin, Thomas F.J.
ORCID
Martin, Thomas F.J.
Venue
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Publisher
Elsevier BV
Published
2015-06
Volume
1851
Issue
6
Pages
785-793
ISSN
1388-1981 (ISSN-L)
DOI
10.1016/j.bbalip.2014.09.017
PMC
PMC4380529
OpenAlex
W2031412125
Cited by
124
References
3
Citations by year
2026: 2 · 2025: 10 · 2024: 4 · 2023: 8 · 2022: 14 · 2021: 11 · 2020: 13 · 2019: 13 · 2018: 9 · 2017: 17 · 2016: 16 · 2015: 7
FWCI
1.34
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (DK025861, DK040428)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
phosphatidylinositol 4,5-bisphosphate, vesicle exocytosis, SNARE proteins, CAPS, Munc13, synaptotagmin-1, C2 domain proteins, syntaxin-1, exocyst complex, Sec3, Exo70, neuroendocrine cells, plasma membrane nanodomains, calcium-triggered exocytosis, vesicle fusion
MeSH terms
Animals, Biological Transport, Calcium, Calcium-Binding Proteins, Exocytosis, Gene Expression Regulation, Nerve Tissue Proteins, Protein Binding, Signal Transduction, Phosphatidylinositol 4,5-Diphosphate, Transport Vesicles, Vesicular Transport Proteins, Syntaxin 1, Synaptotagmin I

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