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Corticotropin-releasing factor-like peptides increase cytosolic [Ca2+] in human epidermoid A-431 cells.
This study investigated whether sauvagine and urotensin I change [Ca2+]i in human epidermoid A-431 cells and whether these changes are correlated with their anti-edema properties in vivo. A-431 cells were used because they possess the corticotropin-releasing factor (CRF) receptor 2. Treatment with either sauvagine or urotensin I led to an immediate increase in [Ca2+]i, the magnitude of which depended on the concentration of the drug. Sauvagine was more effective than urotensin I, with a median effective concentration (EC50) of 1.4 +/- 0.2 fM, compared to an EC50 of 66 +/- 7 fM for urotensin I. Both were more effective at stimulating increases in [Ca2+]i than CRF (EC50 of 6.8 +/- 0.1 pM). There was a correlation between the EC50 for increasing [Ca2+]i and the median effective dose (ED50) for inhibiting edema induced by heating rat paw (r = 0.99). Removal of extracellular Ca2+ or incubation with La3+ eliminated the increase in [Ca2+]i stimulated by either peptide. Pretreatment with a CRF receptor antagonist reduced the increase in [Ca2+]i by these peptides. This occurred in an antagonist concentration-dependent manner, with median inhibitory concentrations (IC50) of 1.99 +/- 0.04 nM and 0.85 +/- 0.04 nM, respectively. Both pertussis toxin (an inhibitor of G proteins) and U-73122 (an inhibitor for inositol trisphosphate (InsP3) production) partially inhibited the increases. InsP3 was measured to determine whether these peptides mobilized Ca2+ from an InsP3-sensitive store. Both sauvagine and urotensin I increased InsP3. The InsP3 increases were inhibited by U-73 122 and CRF antagonist, but not by removal of external Ca2+. Both peptides elevated protein tyrosine phosphorylation. In summary, these peptides increase [Ca2+]i as a result of Ca2+ influx via CRF receptor-operated Ca2+ channels coupled to pertussis toxin-sensitive G proteins and a Ca2+ mobilization from InsP3-sensitive Ca2+ pools. Their in vivo effectiveness at inhibiting edema is related to their respective capacities to stimulate elevations of [Ca2+]i, supporting a role for intracellular Ca2+ in this process.[1]References
- Corticotropin-releasing factor-like peptides increase cytosolic [Ca2+] in human epidermoid A-431 cells. Kiang, J.G. Eur. J. Pharmacol. (1997) [Pubmed]
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