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J. Biol. Chem., Vol. 282, Issue 35, 25349-25356, August 31, 2007

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Lateral Diffusion of the GABA_B Receptor Is Regulated by the GABA_B2 C Terminus^*

From the Medical Research Council Anatomical Neuropharmacology Unit, Mansfield Road, Oxford OX1 3TH, United Kingdom

GABA_B (-aminobutyric acid, type B) is a heterodimeric G-protein-coupled receptor. The GABA_B1 subunit, which contains an endoplasmic reticulum retention sequence, is only transported to the cell surface when it is associated with the GABA_B2 subunit. Fluorescence recovery after photobleaching studies in transfected COS-7 cells and hippocampal neurons revealed that GABA_B2 diffuses slowly within the plasma membrane whether expressed alone or with the GABA_B1 subunit. Treatment of cells with brefeldin A revealed that GABA_B2 moves freely within the endoplasmic reticulum, suggesting that slow movement of GABA_B2 is a result of its plasma membrane insertion. Disruption of the cytoskeleton did not affect the mobility of GABA_B2, indicating that its restricted diffusion is not due to direct interactions with actin or tubulin. To determine whether the C terminus of GABA_B2 regulates its diffusion, this region of the subunit was attached to the lymphocyte membrane protein, CD2, which then exhibited a slower rate of lateral diffusion. Furthermore, co-expression of a cytoplasmically expressed soluble form of the GABA_B2 C terminus increased movement of the GABA_B2 subunit. We constructed forms of GABA_B2 with various C-terminal truncations. Truncation of GABA_B2 after residue 862, but not residue 886, caused a dramatic increase in its mobility, suggesting that the region between these two residues is critical for restricting GABA_B2 diffusion. Finally, we investigated whether activation of GABA_B might modulate its movement. Treatment of COS-7 cells with the GABA_B receptor agonist baclofen significantly increased its mobile fraction. These data show that the restricted movement of GABA_B at the cell surface is regulated by a region within its C terminus.

Received for publication, March 19, 2007 , and in revised form, June 26, 2007.

^* This work was supported by the Medical Research Council and the Blaschko European Visiting Fellowship. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed. Tel.: 44-1865-271-895; Fax: 44-1865-271-647; E-mail: jeff.mcilhinney{at}pharm.ox.ac.uk.

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