Cortisol modulates calcium release-activated calcium channel gating in fish hepatocytes

Abstract

Glucocorticoids (GCs) are rapidly released in response to stress and play an important role in the physiological adjustments to re-establish homeostasis. The mode of action of GCs for stress coping is mediated largely by the steroid binding to the glucocorticoid receptor (GR), a ligand-bound transcription factor, and modulating the expression of target genes. However, GCs also exert rapid actions that are independent of transcriptional regulation by modulating second messenger signaling. However, a membrane-specific protein that transduces rapid GCs signal is yet to be characterized. Here, using freshly isolated hepatocytes from rainbow trout (Oncorhynchus mykiss) and fura2 fluorescence microscopy, we report that stressed levels of cortisol rapidly stimulate the rise in cytosolic free calcium ([Ca2+]i). Pharmacological manipulations using specific extra- and intra-cellular calcium chelators, plasma membrane and endoplasmic reticulum channel blockers and receptors, indicated extracellular Ca2+ entry is required for the cortisol-mediated rise in ([Ca2+]i). Particularly, the calcium release-activated calcium (CRAC) channel gating appears to be a key target for the rapid action of cortisol in the ([Ca2+]i) rise in trout hepatocytes. To test this further, we carried out in silico molecular docking studies using the Drosophila CRAC channel modulator 1 (ORAI1) protein, the pore forming subunit of CRAC channel that is highly conserved. The result predicts a putative binding site on CRAC for cortisol to modulate channel gating, suggesting a direct, as well as an indirect regulation (by other membrane receptors) of CRAC channel gating by cortisol. Altogether, CRAC channel may be a novel cortisol-gated Ca2+ channel transducing rapid nongenomic signalling in hepatocytes during acute stress.

Long-term effects of Omicron BA.2 breakthrough infection on immunity-metabolism balance: a 6-month prospective study

“…Hypothetically, prolactin first increased to regulate cellular immunity and humoral immunity 27 , 28 , and went down along with the recovery condition but took a long time. Cortisol, as an immunosuppressive factor 29 , 30 , and homeostatic stress response regulator 31 did not rise during the early stage but increased at six months to regulate the long-term overactive immune status, and moderate-intensity stress caused by COVID-19 31 . Cortisol may also regulate blood glucose level 29 , 30 to rescue the down-regulated GA.…”

“…But prolactin may be harmful if overactive 28 . Cortisol plays a crucial role in the body’s substance metabolism, homeostatic stress response, immune function and physiological functions of various organs 29 , 30 . Cortisol also plays a key role in regulating stress responses, and hypocortisolism has substantial clinical overlap with COVID-19 symptoms.…”

“…Cortisol has an immunosuppressive effect. It treats conditions caused by an overactive B cell-mediated antibody response 29 , 30 . The increase in cortisol seen at six months of infection may be a protective mechanism against the over activation of the immune response.…”

“…This indicated that glucose metabolism was affected in the long run. Cortisol promotes the activation of glycogen phosphorylase, which is required for the effect of adrenaline on glycogenolysis 29 , 30 . Therefore, changes in cortisol may correlate with both the immunity and the abnormal GA. Lipid metabolism was also disturbed, with the levels of lipase and low-density lipoprotein (LDL) first decreased and then increased at three and six months post BTI, respectively (Fig.…”

Integrated mRNA and miRNA analysis reveals the regulatory network of oxidative stress and inflammation in Coilia nasus brains during air exposure and salinity mitigation

“…These entering Ca 2+ can participate in regulating the activity of enzymes in the mitochondrial respiratory chain [ 65 ]. Increasing cortisol levels caused by stress can rapidly stimulate the increase of cytosolic free Ca 2+ in rainbow trout ( Oncorhynchus mykiss ) [ 66 ]. These results suggested that the obstruction of Ca 2+ transport to the outside cell increases the intracellular Ca 2+ concentration, thus leading to an elevation in mitochondrial Ca 2+ concentration in C. nasus under air exposure.…”