Involvement of ERK1/2 and p38 in Mg2+ accumulation in liver cells

Abstract

Activation of PKC signaling induces Mg(2+) accumulation in liver cells. To test the hypothesis that PKC induces Mg(2+) accumulation via MAPKs activation, hepatocytes were incubated in the presence of PD98059 and SB202190 as specific inhibitors of ERK1/2 and p38, respectively, and stimulated for Mg(2+) accumulation by addition of PMA or OAG. Accumulation of Mg(2+) within the cells was measured by atomic absorbance spectrophotometry in the acid extract of cell pellet. The presence of either inhibitor completely abolished Mg(2+) accumulation irrespective of the dose of agonist utilized while having no discernible effect on beta -adrenoceptor mediated Mg(2+) extrusion. A partial inhibition on alpha (1)-adrenoceptor mediated Mg(2+) extrusion was observed only in cells treated with PD98059. To confirm the inhibitory effect of PD98509 and SB202190, total and basolateral liver plasma membrane vesicles were purified in the presence of either MAPK inhibitor during the isolation procedure. Consistent with the data obtained in intact cells, liver plasma membrane vesicles purified in the presence of PD98509 or SB202190 lost the ability to accumulate Mg(2+)in exchange for intra-vesicular entrapped Na(+) while retaining the ability to extrude entrapped Mg(2+) in exchange for extra-vesicular Na(+). These data indicate that ERK1/2 and p38 are involved in mediating Mg(2+) accumulation in liver cells following activation of PKC signaling. The absence of a detectable effect of either inhibitor on beta -adrenoceptor induced, Na(+)-dependent Mg(2+) extrusion in intact cells and in purified plasma membrane vesicles further support the hypothesis that Mg(2+) extrusion and accumulation occur through distinct and differently regulated transport mechanisms.

Cellular magnesium homeostasis

“…MAPKS) are involved in determining differing cellular responses under seemingly similar stimulatory conditions. Reports from Altura and collaborators in arterial muscle cells [230], Touyz’s laboratory in vascular smooth muscle cells [231], and our group in liver cells [232] indicate that pharmacological inhibition of ERK1/2 and p38 MAPKs abolishes PKC mediated Mg 2+ accumulation [232]. In addition, inhibition of MAPKs signaling hampers Mg 2+ accumulation and affects cyclin activity in vascular smooth muscle cells [231], preventing the cells from progressing in the cell cycle [231].…”

ERK1/2 and p38 MAPKs Are Complementarily Involved in Estradiol 17ß-d-Glucuronide-Induced Cholestasis: Crosstalk with cPKC and PI3K

“…Likely candidates are the mitogen activated protein kinases (MAPKs). Both cPKC [10], [11] and PI3K/Akt [12], [13] often act as upstream signalling activators of MAPKs in hepatocytes.…”

Korean red ginseng and its primary ginsenosides inhibit ethanol-induced oxidative injury by suppression of the MAPK pathway in TIB-73 cells

“…In association with MAPK and [Mg 2+ ], the previous study reported that changes in extracellular and/or intracellular [Mg 2+ ] can modulate the activation of ERK1/2 and affect cell cycle progression and regulation (Touyz and Yao, 2003). Moreover, ERK 1/2 and p38 MAPK play a key role in modulating PKC-induced Mg 2+ accumulation in hepatocytes (Torres et al, 2006). Therefore, the inhibitive effect of KRG, GRg3 and GRh2 on the EtOH-induced decrease in [Mg 2+ ] could correlate with the attenuation of cytotoxicity induced by increased the level of ROS and ERK 1/2 activation.…”