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

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.

Expression of GRINA Correlates with Prognosis in Human Cancers: A Pan-cancer Analysis

“…Reactome pathway analysis showed that insulin receptor recycling, transferrin endocytosis and recycling, attachment of GPI anchor to uPAR, and post-translational modification and synthesis of GPI-anchored proteins were the major pathways associated with the positively co-expressed genes. Cell surface dynamics and post-transcriptional modification of GRINA have also been previously reported [41,53,54]. Noticeably, GO terms and pathways related to genes negatively co-expressed with GRINA were completely different from those related to positively co-expressed genes.…”

“Let Food Be Thy Medicine”: Gluten and Potential Role in Neurodegeneration

“…Encouraged by the cross reactivity between gluten epitopes and human brain antigens, a Blast search was conducted to identify significant peptides’ sequences identity/similarity between both components. The Glutamate Receptor Ionotropic NMDA-Associated Protein 1 (GRINA) belongs to the Lifeguard family and is involved in calcium homeostasis [ 89 ]. This Protein Lifeguard 1, (UniProt: Q7Z429) was identified to have high sequence homology with Gliadin epitopes at identity level of 85.7% ( Table 3 ).…”

Role of Grina/Nmdara1 in the Central Nervous System Diseases

“…In order to understand the characterization of GRINA domains, we analyzed the NCBI’s Conserved Domains Database (CDD) [ 13 ]. GRINA displayed two major domains: a Pro-rich domain (fragment 39-139) within an N- terminal tail and an LFG-like domain (fragment 151-367), belonging to the BI-1-like superfamily, across the transmembrane region [ 14 ].…”

“…This biochemical mechanism would be relevant in the extraintestinal manifestations of SCZ [ 33 ]. Indeed, about one-third of people with SCZ have elevated IgG antibodies to gliadin (AGA IgG) [ 14 ]. Supporting this association, a recent study with 80 healthy controls and 160 patients with SCZ showed that GRINA IgG was higher in SCZ patients than in healthy controls, and that the presence of anti-GRINA antibodies was associated with anti-AGA antibodies [ 8 ].…”

“…Interestingly, ALG2 is among the top RAR-related orphan receptor A (RORA)-linked genes with an elevated expression in the hippocampus of patients with AD [ 65 ]. Furthermore, an alternative splice variant lacking the sequence PPPNPGYPGGPQPPMPPYAQ(fragment 15-34) has been found in AD patients’ cortex (NCBI accession AK294127), but its relevance is still unknown [ 14 ]. Recent observations indicate a decreased cancer risk in patients with AD.…”