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Insights into the role of GPRC5B in the pathophysiology of MLC disease

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Universitat de Barcelona. Departament de Ciències Fisiològiques

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[eng] Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) is a rare genetic disorder characterized by macrocephaly and white matter vacuole formation. The pathogenesis of this disease is suggested to be due to an impaired water and ionic homeostasis by glial cells. MLC disease is caused by mutations in either MLC1 or GLIALCAM genes. They encode for membrane proteins that form a complex in astrocytes, although its exact function is still unclear. GlialCAM has also been reported to act as the auxiliary subunit of the chloride channel ClC-2. In addition, recent studies also identified the G-protein-coupled receptor GPRC5B as an important member of the GlialCAM/MLC1 interactome and relevant to the regulation of related physiological processes. The main objective of this thesis is to determine the role of GPRC5B and signaling events in MLC pathophysiology. We characterized that GPRC5B regulates the expression of a novel GlialCAM/MLC1 interacting protein, Vascular Cell Adhesion Molecule 1 (VCAM-1). Also, we proved that this regulation is dependent on Fyn kinase activity via GPRC5B, and that MLC1 has a negative modulatory effect on this regulation. We also showed that GlialCAM forms oligomeric structures at the plasma membrane of astrocytes via lateral interactions between IgC2 domains from adjacent GlialCAM proteins. Moreover, we propose that mutations in GLIALCAM that encode for residues that are located in GlialCAM IgC2 domain are pathogenic because they increase the stability of GlialCAM oligomeric structures. We give evidence that this endocytosis is physiologically mediated by GPRC5B. Furthermore, we show that phosphorylation events are important in the regulation of the activity of chloride channels within GlialCAM/MLC1 interactome. We observed that GPRC5B has a negative modulatory effect on volume-regulated anion channel (VRAC) activity via Fyn. Last, we identified dephosphorylation events in specific Serine residues in ClC-2 as triggers of the described changes in the subcellular localization of the channel, together with altered gating properties, that occur in astrocytes in depolarizing conditions.

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Tesis Doctorals - Departament - Ciències Fisiològiques

# metadata.dc.title[].value
Insights into the role of GPRC5B in the pathophysiology of MLC disease