Novel regulation of p38 gamma by dopamine D2 receptors during hypoxia

The p38 signalling pathway is part of the MAPK superfamily and is activated by various stressors. Our previous results have shown that two p38 isoform s, p38 alpha and p38 gamma, are activated by hypoxia in the neural-like PC1 2 cell line. PC12 cells also synthesize and secrete catecholamines, includi ng dopamine, in response to hypoxia. We have now used this system to study the interaction between D2-dopamine receptor signalling and the p38 stress- activated protein kinases. Our results show that two D2 receptor antagonist s, butaclamol and sulpiride, enhance hypoxia-induced phosphorylation of p38 gamma, but not p38. This effect persists in protein kinase A (PKA)-deficie nt PC12 cells, demonstrating that p38 gamma modulation by the D2 receptor i s independent of the cAMP/PKA signalling system. We further show that remov al of extracellular calcium blocks the hypoxia-induced increase in p38 gamm a activity. These results are the first to demonstrate that p38 gamma can b e regulated by the D2 receptor and calcium following hypoxic exposure. (C) 2000 Elsevier Science Inc. All rights reserved.