GRINA, also known as Glutamate Receptor Ionotropic NMDA-Associated Protein 1 and TMBIM3, is a member of the Lifeguard family. It is involved in calcium homeostasis, a process that governs key processes like cell survival, neurotransmitter release, and also plays a role in the unfolded protein response and apoptosis regulation [1,2,3,4,6]. It is mainly associated with the membranes of the endoplasmic reticulum, Golgi, endosome, and cell surface [1].

In hepatic ischemia-reperfusion injury (HIRI), hepatocyte-specific Grina knockout exacerbates liver injury, the inflammatory response, and hepatocyte apoptosis, while overexpression mitigates these outcomes. GRINA interacts with ATF6 and recruits HRD1 to form a complex that promotes ATF6 polyubiquitination and degradation, suppressing ER-phagy [3]. In murine transient cerebral ischemia, Grina-deficient mice have earlier and larger infarct demarcations, worse neurological outcomes, and increased apoptosis and activation of the PERK arm of the unfolded protein response compared to wild-type mice [4]. In gastric cancer, knockdown of GRINA decreases the proliferation, migration, invasion capacity, and aerobic glycolysis of cancer cells, and increases apoptosis [5].

In conclusion, GRINA is crucial for maintaining calcium homeostasis, regulating the unfolded protein response, and controlling apoptosis. Studies using Grina knockout mouse models have revealed its role in various disease conditions such as HIRI, cerebral ischemia, and gastric cancer, providing insights into potential therapeutic strategies for these diseases.