2. Academic Validation
  3. Phosphatidylinositol 4-kinase IIα is a glycogen synthase kinase 3-regulated interaction hub for activity-dependent bulk endocytosis

Phosphatidylinositol 4-kinase IIα is a glycogen synthase kinase 3-regulated interaction hub for activity-dependent bulk endocytosis

  • Cell Rep. 2023 Jun 13;42(6):112633. doi: 10.1016/j.celrep.2023.112633.
Eva-Maria Blumrich 1,  Jessica C Nicholson-Fish 2,  Marie Pronot 1,  Elizabeth C Davenport 1,  Dominic Kurian 3,  Adam Cole 4,  Karen J Smillie 5,  Michael A Cousin 6
Affiliations

Affiliations

  • 1 Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, Scotland EH8 9XD, UK; Muir Maxwell Epilepsy Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, Scotland EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, Scotland EH8 9XD, UK.
  • 2 Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, Scotland EH8 9XD, UK.
  • 3 The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Scotland EH25 9RG, UK.
  • 4 Neurosignalling and Mood Disorders Group, The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.
  • 5 Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, Scotland EH8 9XD, UK; Muir Maxwell Epilepsy Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, Scotland EH8 9XD, UK. Electronic address: k.smillie@ed.ac.uk.
  • 6 Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, Scotland EH8 9XD, UK; Muir Maxwell Epilepsy Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, Scotland EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, Scotland EH8 9XD, UK. Electronic address: m.cousin@ed.ac.uk.
PMID: 37314927 DOI: 10.1016/j.celrep.2023.112633
Abstract

Phosphatidylinositol 4-kinase IIα (PI4KIIα) generates essential Phospholipids and is a cargo for endosomal adaptor proteins. Activity-dependent bulk endocytosis (ADBE) is the dominant synaptic vesicle endocytosis mode during high neuronal activity and is sustained by glycogen synthase kinase 3β (GSK3β) activity. We reveal the GSK3β substrate PI4KIIα is essential for ADBE via its depletion in primary neuronal cultures. Kinase-dead PI4KIIα rescues ADBE in these neurons but not a phosphomimetic form mutated at the GSK3β site, Ser-47. Ser-47 phosphomimetic Peptides inhibit ADBE in a dominant-negative manner, confirming that Ser-47 phosphorylation is essential for ADBE. Phosphomimetic PI4KIIα interacts with a specific cohort of presynaptic molecules, two of which, AGAP2 and CAMKV, are also essential for ADBE when depleted in neurons. Thus, PI4KIIα is a GSK3β-dependent interaction hub that silos essential ADBE molecules for liberation during neuronal activity.

Keywords

CP: Cell biology; endocytosis; endosome; kinase; neuron; neurotransmitter; synapse; vesicle.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-103489
    ≥98.0%, PI4KIIα 抑制剂
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