Abstract
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.
Highlights
We review the existing literature about Glutamate Receptor Ionotropic NMDA-Associated Protein 1 (GRINA), and combine it with different software tools to analyze in depth the domains and motifs present in the protein, as well as transcription factors involved in its expression, with the aim of deciphering potential functions, circumstances and mechanisms relevant to GRINA, with an emphasis in mental and neurodegenerative disorders
We found that GRINA is able to interact with Karyopherin β1 (KPNB1) and Calmodulin (CaM), which reinforces our hypothesis that the N-terminal half of GRINA may be able to enter the nucleus, using KPNB1 under resting conditions, and CaM under stress conditions
GRINA can regulate Ca2+ homeostasis by either acting as a channel itself or modulating other proteins like CaV2.2 or IP3Rs, alone or in combination with other members, such as TMBIM6 or CaM
Summary
We review the existing literature about Glutamate Receptor Ionotropic NMDA-Associated Protein 1 (GRINA), and combine it with different software tools to analyze in depth the domains and motifs present in the protein, as well as transcription factors involved in its expression, with the aim of deciphering potential functions, circumstances and mechanisms relevant to GRINA, with an emphasis in mental and neurodegenerative disorders. We present preliminary data about potential ligands of GRINA that reinforce the concepts exposed
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