The RXR-type endoplasmic reticulum-retention/retrieval signal of GABAB1 requires distant spacing from the membrane to function
Abstract
Functional gamma-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.
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RXR motifs enhance the ER localization of ion channels.
“RXR motifs enhance the ER localization of ion channels (Scott et al., 2003; Gassmann et al., 2005).”
From Nicotine up-regulates α4β2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning (2011) · cites this paper as Gassmann et al., 2005
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Srinivasan, R., Pantoja, R., Moss, F. J., Mackey, E. D. W., Son, C. D., Miwa, J., & Lester, H. A. (2011) · Journal of General Physiology · doi:10.1085/jgp.201010532 · Cited by 169 · see citing works
- Authors
- Gassmann, M., Haller, C., Stoll, Y., Aziz, S. A., Biermann, B., Mosbacher, J., Kaupmann, K., & Bettler, B.
- Affiliations
- University of Basel (CH)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 68
- Issue
- 1
- Pages
- 137-144
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W1871703883
- Cited by
- 56
- References
- 37
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 6 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 4
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- coiled-coil dimerization, heteromeric receptor assembly, receptor surface expression, intracellular trafficking, C-terminal tail
- MeSH terms
- Cell Line, Cell Membrane, Endoplasmic Reticulum, Humans, Signal Transduction, Receptors, GABA-B, Retinoid X Receptors
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