Predominant role by CaM kinase in NPY Y(1) receptor signaling: involvement of CREB [corrected].
The role of Ca(2+)/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 cis-CRE and trans-CREB/trans-cFos reporter genes to monitor the role of Ca(2+)/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 2 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.
Sheriff
Sulaiman
S
Department of Surgery, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267, USA. sherifs@email.uc.edu
F  Qureshy
Asbah
A
T  Chance
William
W
Kasckow
John W
JW
Balasubramaniam
Ambikaipakan
A
D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008156:Luciferases / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
D001596:Benzylamines; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D005576:Colforsin; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D007930:Leucine; D008156:Luciferases; D010455:Peptides; D011392:Proline; D016760:Proto-Oncogene Proteins c-fos; D017476:Receptors, Neuropeptide Y; D013449:Sulfonamides; D019284:Thapsigargin; C097212:neuropeptide Y-Y1 receptor; C072105:KN 93; D000096926:Benzenesulfonamides