https://www.nature.com/articles/35077000

Because nicotine can activate AKT via PI3K, we examined the protein levels of Bcl-2 and Bcl-x. We found that treatment with nicotine for 24 h increased the levels of Bcl-2 and Bcl-x, and this was inhibited by LY294002, which indicates the involvement of the PI3K pathway in nicotine-induced Bcl-2 and Bcl-x upregulation.

overexpression of Sig-1Rs significantly up-regulated Bcl-2. Overexpression of Bcl-2 member Mcl-1 in neurons enhanced surface expression of endogenous α7 nAChRs. Furthermore, the activity of several other neuronal nAChR subtypes is also enhanced by NACHO17. Biochemical studies show that NACHO mediates α7 pentamer formation, as NACHO is required for receptor labeling by α-bungarotoxin (α-Bgt)16, which binds at the interface between assembled α7 subunits4,18. Interestingly, resistance to inhibitors of cholinesterase-3 (Ric-3) protein, which is required for nAChR function in Caenorhabditis elegans19, synergizes with NACHO to promote receptor assembly and function16. https://www.nature.com/articles/s41467-019-10723-x

In this manuscript, we demonstrate that S1R is required for biosynthesis of the Atg8 family proteins LC3B, GABARAP, and GABARAPL2. Cells lacking SIGMAR1 show reduced levels of many Atg8-family proteins and impaired autophagic flux.

The intra-α subunit ECD-TMD interface is important to channel function in both human adult and Torpedo nAChR. The transmembrane domain (TMD) of α7nAChR has been identified as a target for positive allosteric modulators (PAMs). https://www.nature.com/articles/s41467-024-46028-x

demonstrating that Nkcc1 overexpression in adult mice restored plasticity to a similar level as observed in the juvenile brain. Activation of TRPV1 by exogenous agonists can increase the expression and function of NKCC1 protein in DRG, which is mediated by activation of PKC/p-ERK signaling pathway. Sigma-1 σ-1 receptor activation inhibits glutamate release from rat cortical nerve terminals. This effect is linked to a decrease in [Ca²⁺](C) caused by Ca²⁺ entry through presynaptic voltage-dependent Ca²⁺ channels and the suppression of the PKC signaling cascade. Furthermore,results suggest that DRG NKCC1 may participate in the inflammatory pain induced by TRPV1. Pursuant to its local anesthetic properties we have shown, for the first time, that nicotine inhibits TTX-resistant sodium channels. In addition, we have also shown, for the first time, that nicotine sensitizes responses to TRPV1 receptors. https://journals.physiology.org/doi/full/10.1152/jn.00922.2003

In all types of nAChRs, agonists such as ACh itself or nicotine-induced ion channel opening and evoke influx of Na and Ca2. Sodium-Channel literature results are consistent with the idea of a sigma-1 protein behaving like either a "chaperone" or a regulatory subunit associated with nNav1.5. Increasing sigma-1 expression to the cells reduced the surface expression of nNav1.5 protein. https://pubmed.ncbi.nlm.nih.gov/23139844/

It is unlikely that nicotine-induced protection against glutamate neurotoxicity is due to its direct action on NMDA receptors though there are some reports indicating that nicotine partially inhibits NMDA receptors. The sigma-1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels in rat hippocampus. Overall, results indicate that Ca2 influx through post-synaptic NMDARs is required for the σR-1 activation to exert the enhancement of the NMDAR currents.

nAChRs, especially α7 nAChRs, generate specific and complex Ca2 signals that include adenylyl cyclase, protein kinase A, protein kinase C, Ca2 -calmodulin-dependent kinase, and phosphatidylinositol 3-kinase (PI3K). Sigma-1, residing mainly at the mitochondria-associated Endoplasmic-Reticulum (ER) membrane (MAM), where it chaperones IP3R3 to ensure proper Ca2 signaling from the endoplasmic reticulum into mitochondria.

The nuclear pore complex (NPC) has been coined “The gate to neurodegenerative diseases”58. Here we report the existence of the first molecular chaperone at the NPC and show that this chaperone, the Sig-1R(Sigma-1 Receptor), being therapeutic for ALS patients. Firstly, we used a human cell line here in the present study. Secondly, we have shown in the past that results from cell lines perfectly mimic the results from rodent brain39,59. https://www.nature.com/articles/s41467-020-19396-3

Immunohistochemistry showed marked loss of nuclear TDP-43, was accompanied by reduction of choline acetyltransferase (ChAT). Choline O-acetyltransferase) is an important enzyme catalyzing the transfer of acetyl group from Acetyl-CoA to choline for synthesis of acetylcholine (ACh), which is a major neurotransmitter in the brain. SIGMAR1 was consistently shown to be co-localized with neuronal nuclear inclusions in TDP-43 proteinopathy, five polyglutamine diseases and INIBD, as well as in intranuclear Marinesco bodies in aged normal controls.

Young hippocampal neurons in α7 nicotinic KO mice have a prolonged period of GABAergic excitation because of delayed appearance of the mature chloride transporter KCC2 and extended presence of the immature chloride transporter NKCC1.

These results suggest that antinociceptive effects of α7 nAChR PAM are associated with downregulation of hippocampal BDNF and p-NKCC1 and upregulation of KCC2 in a mouse model of inflammatory pain. Respectively, nicotine and neurotrophins show similar properties in terms of time-course and signal pathways of neuroprotection. https://www.ncbi.nlm.nih.gov/books/NBK543551/

Results suggest that activation of cholinergic pathway(both muscarinic and nicotinic) restores GABAergic driving force and temporal order recognition deficits in Ngfr−/− (NERVE GROWTH FACTOR KNOCKOUT) mice. Stimulation at sigma-1 receptors by sigma-1 receptor agonists and subsequent interaction with IP3 receptors are involved in the mechanism underlying the potentiation of NGF-induced neurite outgrowth by sigma-1 receptor agonists. https://pmc.ncbi.nlm.nih.gov/articles/PMC2435603/