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The RXR-Type Endoplasmic Reticulum-Retention/Retrieval Signal of GABA_B1 Requires Distant Spacing from the Membrane to Function

Pharmazentrum, University of Basel, Department of Clinical-Biological Sciences, Institute of Physiology, Basel, Switzerland (M.G., C.H., Y.S., B.B., S.A.A., B.B.); and Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland (J.M., K.K.)

Functional -aminobutyric acid type B (GABA_B) receptors are normally only observed upon coexpression of GABA_B1 with GABA_B2 subunits. A C-terminal arginine-based endoplasmic reticulum (ER) retention/retrieval signal, RSRR, prevents escape of unassembled GABA_B1 subunits from the ER and restricts surface expression to correctly assembled heteromeric receptors. The RSRR signal in GABA_B1 is proposed to be shielded by C-terminal coiled-coil interaction of the GABA_B1 with the GABA_B2 subunit. Here, we investigated whether the RSRR motif in GABA_B1 remains functional when grafted to ectopic sites. We found that the RSRR signal in GABA_B1 is inactive in any of the three intracellular loops but remains functional when moved within the distal zone of the C-terminal tail. C-terminal deletions that position the RSRR signal closer to the plasma membrane drastically reduce its effectiveness, supporting that proximity to the membrane restricts access to the RSRR motif. Functional ectopic RSRR signals in GABA_B1 are efficiently inactivated by the GABA_B2 subunit in the absence of coiled-coil dimerization, supporting that coiled-coil interaction is not critical for release of the receptor complex from the ER. The data are consistent with a model in which removal of RSRR from its active zone rather than its direct shielding by coiled-coil dimerization triggers forward trafficking. Because arginine-based intracellular retention signals of the type RXR, where X represents any amino acid, are used to regulate assembly and surface transport of several multimeric complexes, such a mechanism may apply to other proteins as well.

Address correspondence to: Dr. Bernhard Bettler, Pharmazentrum, University of Basel, Klingelbergstr. 50-70, CH-4056 Basel, Switzerland. E-mail: bernhard.bettler{at}unibas.ch

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