Rapid Non-genomic Actions of Cortisol in Fish
Date
2019-12-20
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Abstract
Cortisol, the primary glucocorticoid (GC) in teleosts signals through either the genomic pathway, by activating the intracellular glucocorticoid receptor (GR) and/or the mineralocorticoid receptor (MR), or through non-genomic pathways. However, the mechanism of action of non-genomic cortisol signalling is far from clear, and there is a complete lack of consensus as to the physiological significance of this rapid action. The major goal of this thesis was to determine the mode of action of cortisol in bringing about rapid changes in intracellular Ca2+ levels [iCa2+] as a non-genomic response, and to assess the physiological consequences of this rapid effect at the cellular and organismal level. This was tested using rainbow trout (Oncorhynchus mykiss) hepatocytes (non-excitable) and zebrafish (Danio rerio) muscle (excitable) explant as in vitro and ex vivo models, respectively. The results indicate that a direct interaction of cortisol with the calcium release-activated (CRAC) channel may be responsible for the rapid increase in [iCa2+] due to cortisol. This increase in [iCa2+] with cortisol played a key role in the translocation of intracellular GR to the plasma membrane. This was evident because inhibition of the CRAC channel abolished the colocalization of GR to the caveolin-1 on the plasma membrane of hepatocytes. Cortisol also stimulated a rapid increase in [iCa2+] in zebrafish muscle explants, underscoring a conserved non-genomic role for cortisol in rapidly increasing [iCa2+] in excitable and non-excitable cells. A zebrafish tail-fin amputation model was used to investigate the physiological role of non-genomic and genomic cortisol signalling in regulating epimorphic regeneration. Cortisol rapidly increased [iCa2+] at the amputated site, and this corresponded with an increased ORAI1 (protein subunit of CRAC) expression at the site. Also, an increase in cell proliferation of ORAI1 expressing cells and blastema formation was evident at 24 h in response to cortisol stimulation, but absent in the GR knockout and MR knockout larvae, suggesting that this CRAC channel protein may be both non-genomically and genomically regulated by cortisol. Taken together, this thesis represents a significant contribution to the mechanism of action of rapid non-genomic effects of cortisol, which is essential to our understanding of the role of cortisol in stress adaptation in vertebrates.
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Keywords
Rapid, calcium, channels, cortisol
Citation
Das, C. (2019). Rapid Non-genomic Actions of Cortisol in Fish (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.