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Molecular Pharmacology

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Research ArticleArticle

The RXR-Type Endoplasmic Reticulum-Retention/Retrieval Signal of GABAB1 Requires Distant Spacing from the Membrane to Function

Martin Gassmann, Corinne Haller, Yanick Stoll, Said Abdel Aziz, Barbara Biermann, Johannes Mosbacher, Klemens Kaupmann and Bernhard Bettler
Molecular Pharmacology July 2005, 68 (1) 137-144; DOI: https://doi.org/10.1124/mol.104.010256
Martin Gassmann
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Corinne Haller
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Yanick Stoll
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Said Abdel Aziz
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Barbara Biermann
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Johannes Mosbacher
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Klemens Kaupmann
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Bernhard Bettler
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Abstract

Functional γ-aminobutyric acid type B (GABAB) receptors are normally only observed upon coexpression of GABAB1 with GABAB2 subunits. A C-terminal arginine-based endoplasmic reticulum (ER) retention/retrieval signal, RSRR, prevents escape of unassembled GABAB1 subunits from the ER and restricts surface expression to correctly assembled heteromeric receptors. The RSRR signal in GABAB1 is proposed to be shielded by C-terminal coiled-coil interaction of the GABAB1 with the GABAB2 subunit. Here, we investigated whether the RSRR motif in GABAB1 remains functional when grafted to ectopic sites. We found that the RSRR signal in GABAB1 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 GABAB1 are efficiently inactivated by the GABAB2 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.

  • Received December 14, 2004.
  • Accepted April 1, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 68 (1)
Molecular Pharmacology
Vol. 68, Issue 1
1 Jul 2005
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Research ArticleArticle

The RXR-Type Endoplasmic Reticulum-Retention/Retrieval Signal of GABAB1 Requires Distant Spacing from the Membrane to Function

Martin Gassmann, Corinne Haller, Yanick Stoll, Said Abdel Aziz, Barbara Biermann, Johannes Mosbacher, Klemens Kaupmann and Bernhard Bettler
Molecular Pharmacology July 1, 2005, 68 (1) 137-144; DOI: https://doi.org/10.1124/mol.104.010256

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Research ArticleArticle

The RXR-Type Endoplasmic Reticulum-Retention/Retrieval Signal of GABAB1 Requires Distant Spacing from the Membrane to Function

Martin Gassmann, Corinne Haller, Yanick Stoll, Said Abdel Aziz, Barbara Biermann, Johannes Mosbacher, Klemens Kaupmann and Bernhard Bettler
Molecular Pharmacology July 1, 2005, 68 (1) 137-144; DOI: https://doi.org/10.1124/mol.104.010256
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