GRINA, also known as Glutamate Receptor Ionotropic NMDA-Associated Protein 1 and TMBIM3, is a transmembrane protein involved in calcium homeostasis, a process governing key functions like cell survival and neurotransmitter release. It is associated with membranes of the endoplasmic reticulum, Golgi, endosome, and cell surface. GRINA is part of the Lifeguard family and is involved in the unfolded protein response, controlling apoptosis via regulation of calcium homeostasis [1,2,5].

In hepatic ischemia-reperfusion injury (HIRI), hepatocyte-specific Grina knockout and transgenic mouse models were used. Grina deficiency exacerbated liver injury, the inflammatory response, and hepatocyte apoptosis, while overexpression mitigated these outcomes. GRINA interacted with ATF6 and recruited HRD1 to promote ATF6 polyubiquitination and degradation, suppressing ER-phagy [3]. In murine transient cerebral ischemia, GRINA-deficient (Grina-/ -) mice had earlier and larger infarct demarcations, a worse neurological outcome, and abolished EPO-mediated neuroprotection compared to wild-type mice. GRINA-deficiency also increased apoptosis and activation of the PERK arm of the unfolded protein response [4].

In conclusion, GRINA plays a crucial role in maintaining calcium homeostasis, regulating the unfolded protein response, and controlling apoptosis. Studies using Grina knockout mouse models have revealed its significance in diseases such as HIRI and cerebral ischemia, highlighting its potential as a therapeutic target for these conditions.

References:

1. Jiménez-González, Víctor, Ogalla-García, Elena, García-Quintanilla, Meritxell, García-Quintanilla, Albert. 2019. Deciphering GRINA/Lifeguard1: Nuclear Location, Ca2+ Homeostasis and Vesicle Transport. In International journal of molecular sciences, 20, . doi:10.3390/ijms20164005. https://pubmed.ncbi.nlm.nih.gov/31426446/

2. Mallmann, Robert Theodor, Moravcikova, Lucia, Ondacova, Katarina, Lacinova, Lubica, Klugbauer, Norbert. 2019. Grina/TMBIM3 modulates voltage-gated CaV2.2 Ca2+ channels in a G-protein-like manner. In Cell calcium, 80, 71-78. doi:10.1016/j.ceca.2019.04.002. https://pubmed.ncbi.nlm.nih.gov/30991297/

3. Yu, Hongjun, Wang, Chaoqun, Qian, Baolin, Fu, Yao, Ma, Yong. 2025. GRINA alleviates hepatic ischemia‒reperfusion injury-induced apoptosis and ER-phagy by enhancing HRD1-mediated ATF6 ubiquitination. In Journal of hepatology, , . doi:10.1016/j.jhep.2025.01.012. https://pubmed.ncbi.nlm.nih.gov/39855351/

4. Habib, Pardes, Stamm, Ann-Sophie, Schulz, Joerg B, Huber, Michael, Wilhelm, Thomas. 2019. EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia. In International journal of molecular sciences, 20, . doi:10.3390/ijms20215421. https://pubmed.ncbi.nlm.nih.gov/31683519/

5. Rojas-Rivera, D, Armisén, R, Colombo, A, Stutzin, A, Hetz, C. 2012. TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis. In Cell death and differentiation, 19, 1013-26. doi:10.1038/cdd.2011.189. https://pubmed.ncbi.nlm.nih.gov/22240901/