Stromal Interaction Molecule 1-Mediated Store-Operated Calcium Entry Promotes Autophagy Through AKT/Mammalian Target of Rapamycin Pathway in Hippocampal Neurons After Ischemic Stroke

pathophysiological process of neuronal injury due to cerebral ischemia is complex among which disturbance of calcium homeostasis and autophagy are two major pathogenesis. However, it remains ambiguous whether the two factors are independent. Stromal interaction molecule 1 (STIM1) is the most important Ca2+ sensor mediating the store-operated Ca2+ entry (SOCE) through interacting with Orai1 and has recently been proven to participate in autophagy in multiple cells. In this study, we aimed to investigate the potential role of STIM1induced SOCE on autophagy and whether its regulator function contributes to neuronal injury under hypoxic conditions using in vivo transient middle cerebral artery occlusion (tMCAO) model and in vitro oxygen and glucose deprivation (OGD) primary cultured neuron model respectively. The present data indicated that STIM1 induces autophagic flux impairment in neurons through promoting SOCE and inhibiting AKT/mTOR signaling pathway. Pharmacological inhibition of SOCE or downregulation of STIM1 with siRNA suppressed the autophagic activity in neurons. Moreover, stim1 knockdown attenuated neurological deficits and brain damage after tMCAO, which could be reversed by AKT/mTOR pathway inhibitor AZD5363. Together, the modulation of STIM1 on autophagic activation indicated the potential link between Ca2+ homeostasis and autophagy which provided evidence that STIM1 could be a promising therapeutic target for ischemic stroke.(c) 2023 The Author(s). Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

The pathophysiological process of neuronal injury due to cerebral ischemia involves disturbances in calcium homeostasis and autophagy. STIM1 has been identified as an important Ca2+ sensor that mediates store-operated Ca2+ entry (SOCE) and is also involved in autophagy. This study found that STIM1 induces impairment of autophagic flux in neurons by promoting SOCE and inhibiting the AKT/mTOR signaling pathway. Inhibition of SOCE or downregulation of STIM1 suppresses autophagic activity in neurons. Moreover, knockdown of stim1 attenuates neurological deficits and brain damage caused by cerebral ischemia, which can be reversed by an AKT/mTOR pathway inhibitor. These findings suggest that STIM1 could be a potential therapeutic target for ischemic stroke.