Adenosine A(2A) receptor mRNA regulation by nerve growth factor is TrkA-, Src-, and Ras-dependent via extracellular regulated kinase and stress-activated protein kinase/c-Jun NH2-terminal kinase

We have shown previously that nerve growth factor (NGF) down-regulates aden osine A(2A) receptor (A(2A)AR) mRNA in PC12 cells, To define cellular mecha nisms that modulate A(2A)AR expression, A(2A)AR mRNA and protein levels wer e examined in three PC12 sublines: i) PC12nnr5 cells, which lack the high a ffinity NGF receptor TrkA, ii) srcDN2 cells, which overexpress kinase-defec tive Src, and iii) 17.26 cells, which overexpress a dominant-inhibitory Ras , In the absence of functional TrkA, Src, or Ras, NGF-induced down-regulati on of A(2A)AR mRNA and protein was significantly impaired. However, regulat ion of A(2A)AR expression was reconstituted in PC12nnr5 cells stably transf ected with TrkA. Whereas NGF stimulated the mitogen-activated protein kinas es p38, extracellular regulated kinase 1 and 2 (ERK1/ERK2), and stress-acti vated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) in PC12 cells, th ese kinases were activated only partially or not at all in srcDN2 and 17.26 cells. Inhibiting ERK1/ERK2 with PD98059 or inhibiting SAPK/JNK by transfe cting cells with a dominant-negative SAPK beta/JNK3 mutant partially blocke d NGF-induced down-regulation of A(2A)AR expression in PC12 cells, In contr ast, inhibiting p38 with SB203580 had no effect on the regulation of A(2A)A R mRNA and protein levels. Treating SAPK beta/JNK3 mutant-transfected PC12 cells with PD98059 completely abolished the NGF-induced decrease in A(2A)AR mRNA and protein levels, These results reveal a role for ERK1/ERK2 and SAP K/JNK in regulating A(2A)AR expression.