ARMET/MANF Protein, Human (His)

ARMET/MANF protein selectively promotes the survival of dopaminergic neurons in the ventral mid-brain, thereby playing a crucial role in neuronal homeostasis. It modulates GABAergic transmission to dopaminergic neurons in the substantia nigra, enhancing both spontaneous and evoked GABAergic inhibitory postsynaptic currents, indicating its involvement in neurotransmission regulation (By similarity). Additionally, ARMET/MANF inhibits cell proliferation and protects against endoplasmic reticulum (ER) stress-induced cell death, demonstrating its multifaceted role in cellular processess. Under normal conditions, the protein is retained in the ER/sarcoplasmic reticulum (SR) through its association with the endoplasmic reticulum chaperone protein HSPA5. However, in response to ER stress and hypoxia, ARMET/MANF is upregulated and secreted by the ER/SR, leading to its binding to 3-O-sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane of target cells. This interaction facilitates cellular uptake through endocytosis and is crucial for ARMET/MANF's role in alleviating ER stress and mitigating cell toxicity under hypoxic and ER stress conditions. The protein also interacts directly with HSPA5 and is part of a complex involving CRELD2, MANF, MATN3, and PDIA4, further underscoring its involvement in cellular regulatory networks (By similarity).