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The Journal of Neuroscience, October 6, 2004, 24(40):8752-8761; doi:10.1523/JNEUROSCI.3155-04.2004

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Cellular/Molecular
Ral and Phospholipase D2-Dependent Pathway for Constitutive Metabotropic Glutamate Receptor Endocytosis

Moshmi Bhattacharya,^1 * Andy V. Babwah,^1 * Christina Godin,¹ Pieter H. Anborgh,¹ Lianne B. Dale,¹ Michael O. Poulter,³ and Stephen S. G. Ferguson^1,2

¹Cell Biology Research Group, Robarts Research Institute, London, Ontario, Canada N6A 5K8, ²Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A 5C1, and ³Neuroscience Research Institute, Carleton University, Ottawa, Ontario, Canada K1S 5B6

G-protein-coupled receptors play a central role in the regulation of neuronal cell communication. Class 1 metabotropic glutamate receptors (mGluRs) mGluR1a and mGluR5a, which are coupled with the hydrolysis of phosphoinositides, are essential for modulating excitatory neurotransmission at glutamatergic synapses. These receptors are constitutively internalized in heterologous cell cultures, neuronal cultures, and intact neuronal tissues. We show here that the small GTP-binding protein Ral, its guanine nucleotide exchange factor RalGDS (Ral GDP dissociation stimulator), and phospholipase D2 (PLD2) are constitutively associated with class 1 mGluRs and regulate constitutive mGluR endocytosis. Moreover, both Ral and PLD2 are colocalized with mGluRs in endocytic vesicles in both human embryonic kidney 293 (HEK 293) cells and neurons. Ral and PLD2 activity is required for the internalization of class 1 mGluRs but is not required for the internalization of the ₂-adrenergic receptor. Constitutive class 1 mGluR internalization is not dependent on the downstream Ral effector proteins Ral-binding protein 1 and PLD1 or either ADP-ribosylation factors ARF1 or ARF6. The treatment of HEK 293 cells and neurons with small interfering RNA both downregulates PLD2 expression and blocks mGluR1a and mGluR5a endocytosis. The constitutive internalization of mGluR1a and mGluR5a is also attenuated by the treatment of cells with 1-butanol to prevent PLD2-mediated phosphatidic acid formation. We propose that the formation of a mGluR-scaffolded RalGDS/Ral/PLD2 protein complex provides a novel alternative mechanism to -arrestins for the constitutive endocytosis of class 1 mGluRs.

Key words: G-protein-coupled receptor; Ral GTP-binding protein; phospholipase D; endocytosis; metabotropic glutamate receptor; glutamate

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Received April 8, 2004; revised August 18, 2004; accepted August 19, 2004.

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