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Ursodeoxycholate mobilizes intracellular calcium and activates phosphorylase alpha in isolated hepatocytes



Ursodeoxycholate mobilizes intracellular calcium and activates phosphorylase alpha in isolated hepatocytes



American Journal of Physiology 264(2 PART 1): G243-G251



In isolated hamster hepatocytes, ursodeoxycholic acid (UDCA) mobilized intracellular free calcium ((Ca-2+)-i) and activated phosphorylase a with a half-maximally effective concentration of 188 and 9 mu-M, respectively. Addition of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) did not affect the maximum (Ca-2+)-i mobilized by UDCA; however, (Ca-2+)-i returned to basal levels in 4-5 min compared with gt 10 min in the absence of EGTA. Both UDCA and vasopressin activated phosphorylase a to the same extent in the presence and absence of extracellular Ca-2+, and the effect of both agents was abolished when the cells were depleted in Ca-2+. Vasopressin (100 nM) did not further mobilize (Ca-2+)-i or active phosphorylase a when combined with 500 mu-M UDCA. However, unlike vasopressin, UDCA did not stimulate inositol 1,4,5-trisphosphate (IP-3) formation. In contrast to taurine-conjugated UDCA (TUDCA), concentrations ltoreq 500 mu-M of glycine-conjugated UDCA (GUDCA) did not affect either (Ca-2+)-i or phosphorylase a. Lithocholic acid and taurolithocholic acid (TLCA) displayed the highest affinity for Ca-2+. In addition, TLCA, chenodeoxycholic acid, and NaF stimulated Ca-2+ efflux at concentrations as low as 100 mu-M, 200 mu-M, and 5 mM, respectively. Conversely, UDCA, TUDCA, and GUDCA presented the lowest affinity for Ca-2+ and had no effect on Ca-2+ efflux. The 28% increase in Ca-2+ release induced by TLCA alone was further augmented to apprx 60% when TLCA was combined with UDCA, TUDCA, or GUDCA. However, Ca-2+ efflux induced by NaF was not further increased by UDCA and its conjugates. These studies suggest that UDCA activates phosphorylase a through an IP-3-independent Ca-2+-dependent mechanism. Furthermore, UDCA presents a low affinity for Ca-2+ and does not stimulate Ca-2+ efflux.

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Accession: 009702046

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