Endocytic trafficking of neurotransmitter receptors is critical to neuronal signaling and activity-dependent synaptic plasticity. Although the importance of clathrin-mediated endocytosis in receptor trafficking in neurons is well established, the contribution of the caveolar/ lipid raft pathway has been little explored. Here, we show that caveolin-1, an adaptor protein that associates with lipid rafts and the main coat protein of caveolae, binds to and colocalizes with metabotropic glutamate receptors 1/5 (mGluR1/5). The interaction with caveolin-1 controls the rate of constitutive mGluR1 internalization, thereby regulating expression of the receptor at the cell surface. Consistent with a role for caveolin-1 in mGluR trafficking, we show that mGluR1/5 associate with lipid rafts in the brain and that their constitutive internalization is mediated, in both heterologous cells and neurons, by caveolar/raft-dependent endocytosis. We further show that caveolin-1 attenuates mGluR1-dependent activation of extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) signaling, an effect that is abolished in cells expressing mutant mGluR1 lacking intact caveolin binding motifs. Neurons from caveolin-1 knock-out mice show enhanced basal ERK1/2 phosphorylation and prolonged ERK1/2 activation in response to stimulation with DHPG [(RS)-3,5-dihydroxyphenylglycine], a group I mGluR-selective agonist. Together, these findings underscore the importance of caveolar rafts in neurons and suggest that this pathway might play an important role in synapse formation and plasticity.
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