Alterations in mitochondria and increased oxidative stress are associated with the disease progression in Huntington's disease (HD). Endoplasmic reticulum (ER) stress and oxidative damage are linked through the close communication between the ER and mitochondria. Sigma-1 receptor (Sig-1R) is a chaperone protein in the ER that is involved in ER stress regulation, but little is known about its role in HD or the mechanisms for cell protection. Here we show that the Sig-1R agonist, PRE084 increases cell survival and counteracts the deleterious effects caused by N-terminal mutant huntingtin proteins in neuronal PC6.3 cells. Particularly, PRE084 increased the levels of cellular antioxidants by activating the NF-κB pathway that is compromised by the expression of mutant huntingtin proteins. These results show that the Sig-1R agonist has beneficial effects in models of HD and that compounds affecting the Sig-1R may be promising targets for future drug development in HD.

Background:The identity of calcium channels in the thyroid is undefined. Results: TRPC1 functions as a major regulator of S1P and VEGF receptors via a calcium-dependent mechanism. This is important for cell migration. Conclusion:We have defined a novel physiological role for the TRPC1 channel. Significance: This study explains how TRPC1 regulates receptor expression and migration in thyroid cancer cells.

Highlights d Seipin is enriched at ER-MAMs d Seipin interacts with MAM calcium regulators in a nutritionally regulated manner d Adipocyte seipin deficiency impairs mitochondrial calcium import and ATP production d Inducible seipin removal from adipose tissue leads to rapid mitochondrial dysfunction

Transient receptor potential (TRP) cation channels are widely expressed and function in many physiologically important processes. Perturbations in the expression or mutations of the channels have implications for diseases. Many thyroid disorders, as excessive growth or disturbed thyroid hormone production, can be a result of dysregulated TSH signaling. In the present study, we found that of TRP canonicals (TRPCs), only TRPC2 was expressed in Fischer rat thyroid low-serum 5% cells (FRTL-5 cells). To investigate the physiological importance of the channel, we developed stable TRPC2 knockdown cells using short hairpin RNA (shTRPC2 cells). In these cells, the ATP-evoked entry of calcium was significantly decreased. This led to increased cAMP production, because inhibitory signals from calcium to adenylate cyclase 5/6 were decreased. Enhanced cAMP signaling projected to Ras-related protein 1-MAPK kinase 1 (MAPK/ERK kinase 1) pathway leading to phosphorylation of ERK1/2. The activated ERK1/2 pathway increased the expression of the TSH receptor. In contrast, secretion of thyroglobulin was decreased in shTRPC2 cells, due to improper folding and glycosylation of the protein. We show here a novel role for TRPC2 in regulating thyroid cell function.

Oxysterol-binding protein related-protein 5 and 8 (ORP5/8) localize to the membrane contact sites (MCS) of the endoplasmic reticulum (ER) and the mitochondria, as well as to the ER-plasma membrane (PM) MCS. The MCS are emerging as important regulators of cell signaling events, including calcium (Ca) signaling. ORP5/8 have been shown to interact with phosphatidylinositol-4,5-bisphosphate (PIP) in the PM, and to modulate mitochondrial respiration and morphology. PIP is the direct precursor of inositol trisphosphate (IP), a key second messenger responsible for Ca-release from the intracellular Ca stores. Further, mitochondrial respiration is linked to Ca transfer from the ER to the mitochondria. Hence, we asked whether ORP5/8 would affect Ca signaling in these cell compartments, and employed genetically engineered aequorin Ca probes to investigate the effect of ORP5/8 in the regulation of mitochondrial and caveolar Ca. Our results show that ORP5/8 overexpression leads to increased mitochondrial matrix Ca as well as to increased Ca concentration at the caveolar subdomains of the PM during histamine stimulation, while having no effect on the cytoplasmic Ca. Also, we found that ORP5/8 overexpression increases cell proliferation. Our results show that ORP5/8 regulate Ca signaling at specific MCS foci. These local ORP5/8-mediated Ca signaling events are likely to play roles in processes such as mitochondrial respiration and cell proliferation.