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The Journal of Neuroscience, March 18, 2009, 29(11):3590-3602; doi:10.1523/JNEUROSCI.5824-08.2009

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Development/Plasticity/Repair
Regulation of Group I Metabotropic Glutamate Receptor Trafficking and Signaling by the Caveolar/Lipid Raft Pathway

Anna Francesconi, Ranju Kumari, and R. Suzanne Zukin

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Correspondence should be addressed to Anna Francesconi, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Email: afrances{at}aecom.yu.edu

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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Received Dec. 5, 2008; revised Jan. 18, 2009; accepted Jan. 21, 2009.

Correspondence should be addressed to Anna Francesconi, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Email: afrances{at}aecom.yu.edu

This article has been cited by other articles:

				J. A. Allen, J. Z. Yu, R. H. Dave, A. Bhatnagar, B. L. Roth, and M. M. Rasenick Caveolin-1 and Lipid Microdomains Regulate Gs Trafficking and Attenuate Gs/Adenylyl Cyclase Signaling Mol. Pharmacol., November 1, 2009; 76(5): 1082 - 1093. [Abstract] [Full Text] [PDF]

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