4.5 Article

Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins

期刊

HUMAN MOLECULAR GENETICS
卷 30, 期 17, 页码 1649-1665

出版社

OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddab155

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资金

  1. MICINN [SAF 2015-70377, RTI2018-093493-B-I00]
  2. ISCIII (ERARE)
  3. Icrea Academia prizes
  4. 'Fondation pour la recherche medicale' [PLP20170939025p60, AJE20171039094]
  5. European Leukodystrophies Association (ELA International) Research Foundation [2019-010 C4A]
  6. Spanish Health Institute Carlos III Grant [PI16/00267-R-FEDER]
  7. Generalitat de Catalunya [SGR2017-191, 2017SGR737]
  8. CERCA Programme/Generalitat de Catalunya
  9. European Union
  10. Fondo Europeo de Desarrollo regional, Ministerio de Ciencia e Innovacion
  11. Instituto de Salud Carlos III of Spain [FIS P17/00296]
  12. RETICS Oftared [RD16/0008/0014]
  13. Maria de Maeztu [MDM-2017-0729]

向作者/读者索取更多资源

MLC is a vacuolating leukodystrophy primarily caused by mutations in MLC1 or GLIALCAM genes, with the brain GlialCAM interacting proteome involving various proteins related to brain homeostasis regulation, including G protein-coupled receptors.
Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a type of vacuolating leukodystrophy, which is mainly caused by mutations in MLC1 or GLIALCAM. The two MLC-causing genes encode for membrane proteins of yet unknown function that have been linked to the regulation of different chloride channels such as the ClC-2 and VRAC. To gain insight into the role of MLC proteins, we have determined the brain GlialCAM interacting proteome. The proteome includes different transporters and ion channels known to be involved in the regulation of brain homeostasis, proteins related to adhesion or signaling as several G protein-coupled receptors (GPCRs), including the orphan GPRC513 and the proposed prosaposin receptor GPR37L1. Focusing on these two GPCRs, we could validate that they interact directly with MLC proteins. The inactivation of Gpr3711 in mice upregulated MLC proteins without altering their localization. Conversely, a reduction of GPRC513 levels in primary astrocytes downregulated MLC proteins, leading to an impaired activation of ClC-2 and VRAC. The interaction between the GPCRs and MLC1 was dynamically regulated upon changes in the osmolarity or potassium concentration. We propose that G1ia1CAM and MLC1 associate with different integral membrane proteins modulating their functions and acting as a recruitment site for various signaling components as the GPCRs identified here. We hypothesized that the GlialCAM/MLC1 complex is working as an adhesion molecule coupled to a tetraspanin-like molecule performing regulatory effects through direct binding or influencing signal transduction events.

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