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Int J Mol Sci. 2019 Aug 16;20(16). pii: E4005. doi: 10.3390/ijms20164005.

Deciphering GRINA/Lifeguard1: Nuclear Location, Ca2+ Homeostasis and Vesicle Transport.

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Department of Pharmacology, School of Pharmacy, University of Seville, 41012 Seville, Spain.
Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain.
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Seville, 41012 Seville, Spain.


The Glutamate Receptor Ionotropic NMDA-Associated Protein 1 (GRINA) belongs to the Lifeguard family and is involved in calcium homeostasis, which governs key processes, such as cell survival or the release of neurotransmitters. GRINA is mainly associated with membranes of the endoplasmic reticulum, Golgi, endosome, and the cell surface, but its presence in the nucleus has not been explained yet. Here we dissect, with the help of different software tools, the potential roles of GRINA in the cell and how they may be altered in diseases, such as schizophrenia or celiac disease. We describe for the first time that the cytoplasmic N-terminal half of GRINA (which spans a Proline-rich domain) contains a potential DNA-binding sequence, in addition to cleavage target sites and probable PY-nuclear localization sequences, that may enable it to be released from the rest of the protein and enter the nucleus under suitable conditions, where it could participate in the transcription, alternative splicing, and mRNA export of a subset of genes likely involved in lipid and sterol synthesis, ribosome biogenesis, or cell cycle progression. To support these findings, we include additional evidence based on an exhaustive review of the literature and our preliminary data of the protein-protein interaction network of GRINA.


GRINA/TMBIM3/LFG1; Proline-rich domain; alternative splicing; calcium homeostasis; endoplasmic reticulum stress; endosome-to-Golgi retrieval; interactome; nucleolus; sterol; vesicle

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