In Rat-1 fibroblasts, endothelin-1 and a protein kinase C-stimulating phorbol ester stimulated extracellular signal-regulated kinase (ERK), whereas phenylephrine, acting at stably transfected human alpha1A-adrenoceptors, inhibited basal and endothelin-1- and phorbol ester-stimulated ERK. On the other hand, phenylephrine stimulated p38 mitogen-activated protein kinase (MAPK). Anisomycin caused p38 activation and ERK inhibition quantitatively similar to those produced by phenylephrine. SB 203,580, an inhibitor of p38, significantly attenuated phenylephrine- and anisomycin-induced ERK inhibition. The ERK inhibition by phenylephrine was not affected by the cytosolic phospholipase A2 inhibitor arachidonyltrifluoromethyl ketone or the cyclooxygenase inhibitor indomethacin but was significantly attenuated by a combination of the phosphatase inhibitors Na3VO4 and okadaic acid. Neither SB 203,580 nor the phosphatase inhibitors significantly affected ERK inhibition by the adenylyl cyclase activator forskolin. We conclude that there is a previously unrecognized interaction between ERK and p38 MAPK, in which activation of p38 causes inhibition of ERK; this may at least partly involve MAPK phosphatases that inactivate ERK.
Patients with chronic renal failure exhibit multiple endocrine, gastrointestinal and cardiovascular abnormalities, many of which may be explained by alterations of adenylyl cyclase (AC) responsiveness and/or G-protein expression. Since such alterations were previously reported, e.g., for platelets of adult chronic renal failure patients undergoing hemodialysis treatment (HD), we have investigated whether children with chronic renal failure undergoing HD exhibit similar alterations. Eleven uremic children undergoing HD were compared with 11 age-matched healthy controls. Platelet AC activity was determined in the absence (basal) and presence of a receptor agonist, direct G-protein activators and direct AC stimulators. G-protein alpha-subunits were measured by quantitative immunoblotting. Basal and stimulated platelet AC and immunoreactivity for platelet G-protein alpha-subunits did not significantly differ between HD and control children. We conclude that HD in children is associated with much smaller, if any, abnormalities of blood cell signal transduction than in adult patients. We speculate that quality of dialysis, age, and underlying disease might differentially influence blood cell signal transduction cascades.
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