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The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses.

ABSTRACT: Single point mutations or variations in the expression of the gene encoding the neuronal glycoprotein M6a have been associated with psychiatric disorders such as Alzheimer's disease, depression and schizophrenia. In cultured neurons, M6a positively contributes to neurite extension, axon guidance, filopodia/spine outgrowth, and synapse formation. The endocytic processes of neuronal membrane proteins are linked to the differentiation, growth, signaling and plasticity of neurons. However, the roles of M6a and the precise mechanisms through which M6a internalizes and recycles back to the neuronal membrane are unknown. Here, by using a controlled in vitro assay, we showed that if 30-40% of M6a is endocytosed, the number of synapses in hippocampal neurons decreases. When re-establishing the levels of M6a at the cell surface, the number of synapses returned to normal values. M6a internalization involves clathrin-coated pits, probably by association between the adaptor protein 2 and the 251YEDI254 "tyrosine-based" motif located within the C-tail of M6a. Upon endocytosis, M6a is sorted to early endosome antigen 1- and Rab5-positive endosomes and then sorted back to the cell surface via Rab11-positive endosomes or to degradation via Rab7 and, finally LAMP-1-positive endosomes. Our results demonstrated that the levels of M6a at the cell surface modified the formation/maintenance of synapses, without altering the protein levels of synaptophysin or N-methyl-D-aspartate receptor type-1. This novel mechanism might be relevant during neuronal development, pruning and/or many of the neurological disorders in which the number of synapses is affected.

SUBMITTER: Garcia MD

PROVIDER: S-EPMC5611492 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses.

Garcia Micaela D MD Formoso Karina K Aparicio Gabriela I GI Frasch Alberto C C ACC Scorticati Camila C

Frontiers in molecular neuroscience 20170920

Single point mutations or variations in the expression of the gene encoding the neuronal glycoprotein M6a have been associated with psychiatric disorders such as Alzheimer's disease, depression and schizophrenia. In cultured neurons, M6a positively contributes to neurite extension, axon guidance, filopodia/spine outgrowth, and synapse formation. The endocytic processes of neuronal membrane proteins are linked to the differentiation, growth, signaling and plasticity of neurons. However, the roles ...[more]

PMID: 28979185

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Project description:Several studies have suggested crosstalk between different clathrin-independent endocytic pathways. However, the molecular mechanisms and functional relevance of these interactions are unclear. Caveolins and cavins are crucial components of caveolae, specialized microdomains that also constitute an endocytic route. Here we show that specific caveolar proteins are independently acting negative regulators of clathrin-independent endocytosis. Cavin-1 and Cavin-3, but not Cavin-2 or Cavin-4, are potent inhibitors of the clathrin-independent carriers/GPI-AP enriched early endosomal compartment (CLIC/GEEC) endocytic pathway, in a process independent of caveola formation. Caveolin-1 (CAV1) and CAV3 also inhibit the CLIC/GEEC pathway upon over-expression. Expression of caveolar protein leads to reduction in formation of early CLIC/GEEC carriers, as detected by quantitative electron microscopy analysis. Furthermore, the CLIC/GEEC pathway is upregulated in cells lacking CAV1/Cavin-1 or with reduced expression of Cavin-1 and Cavin-3. Inhibition by caveolins can be mimicked by the isolated caveolin scaffolding domain and is associated with perturbed diffusion of lipid microdomain components, as revealed by fluorescence recovery after photobleaching (FRAP) studies. In the absence of cavins (and caveolae) CAV1 is itself endocytosed preferentially through the CLIC/GEEC pathway, but the pathway loses polarization and sorting attributes with consequences for membrane dynamics and endocytic polarization in migrating cells and adult muscle tissue. We also found that noncaveolar Cavin-1 can act as a modulator for the activity of the key regulator of the CLIC/GEEC pathway, Cdc42. This work provides new insights into the regulation of noncaveolar clathrin-independent endocytosis by specific caveolar proteins, illustrating multiple levels of crosstalk between these pathways. We show for the first time a role for specific cavins in regulating the CLIC/GEEC pathway, provide a new tool to study this pathway, identify caveola-independent functions of the cavins and propose a novel mechanism for inhibition of the CLIC/GEEC pathway by caveolin.

Dataset Information

The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses.

Publications

The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses.

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