Predominant role by CaM kinase in NPYY1 receptor signaling: Involvement of CREB and ambikaipakan

The role of Ca2+/cAMP-dependent signal transduction and transcription factor CREB in mediating NPY- Y-1 receptor function was investigated in SK-N-MC cells. The Y-1 receptor agonist, [Leu(31),Pro(34)]-NPY, inhibited forskolin-stimulated cAMP production which was insensitive to thapsigargin or the CaM kinase II inhibitor, KN-93. Although activation of the Y-1 receptor leads to an increase in CREB phosphorylation, [Leu(31).Pro(34)]-NPY inhibited CREB phosphorylation in KN-93-treated cells. SK-N-MC cells were also transfected with PathDetect(R) cis-CRE and trans-CREB/trans-cFos reporter genes to monitor the role of Ca2+/cAMP signals, triggered by Y-1 receptor, on reporter gene activity. Treatment of the cis-CRE-luciferase expression vector-transfected cells with [Leu(31).Pro(34)]-NPY increased reporter gene activity by similar to2 fold through a KN-93 sensitive pathway. In contrast, the peptide inhibited forskolin-stimulated luciferase activity. Consistently. [Leu(31),Pro(34)]-NPY induced trans-CREB mediated luciferase activity through a CaM kinase dependent pathway, and inhibited forskolin-stimulated luciferase gene expression. However, no effect of the peptide was observed on trans-cFos- mediated luciferase activity. These findings suggest that the NPY Y-1 receptor induces the expression of CRE containing target genes through the CaM kinase-CREB pathway. and inhibits CRE containing genes when cellular cAMP levels are elevated. (C) 2002 Elsevier Science Inc. All rights reserved.