Regulation of group I metabotropic glutamate receptor trafficking and signaling by the caveolar/lipid raft pathway.
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.
Francesconi
Anna
A
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA. afrances@aecom.yu.edu
Kumari
Ranju
R
Zukin
R Suzanne
RS
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D051242:Caveolin 1 / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology
D051242:Caveolin 1; D018091:Receptors, AMPA; C495540:CAV1 protein, human