PMID- 28451751 OWN - NLM STAT- MEDLINE DCOM- 20181224 LR - 20191008 IS - 1432-0878 (Electronic) IS - 0302-766X (Print) IS - 0302-766X (Linking) VI - 369 IP - 3 DP - 2017 Sep TI - Natriuretic peptide activation of extracellular regulated kinase 1/2 (ERK1/2) pathway by particulate guanylyl cyclases in GH3 somatolactotropes. PG - 567-578 LID - 10.1007/s00441-017-2624-x [doi] AB - The natriuretic peptides, Atrial-, B-type and C-type natriuretric peptides (ANP, BNP, CNP), are regulators of many endocrine tissues and exert their effects predominantly through the activation of their specific guanylyl cyclase receptors (GC-A and GC-B) to generate cGMP. Whereas cGMP-independent signalling has been reported in response to natriuretic peptides, this is mediated via either the clearance receptor (Npr-C) or a renal-specific NPR-Bi isoform, which both lack intrinsic guanylyl cyclase activity. Here, we report evidence of GC-B-dependent cGMP-independent signalling in pituitary GH3 cells. Stimulation of GH3 cells with CNP resulted in a rapid and sustained enhancement of ERK1/2 phosphorylation (P-ERK1/2), an effect that was not mimicked by dibutryl-cGMP. Furthermore, CNP-stimulated P-ERK1/2 occurred at concentrations below that required for cGMP accumulation. The effect of CNP on P-ERK1/2 was sensitive to pharmacological blockade of MEK (U0126) and Src kinases (PP2). Silencing of the GC-B1 and GC-B2 splice variants of the GC-B receptor by using targeted short interfering RNAs completely blocked the CNP effects on P-ERK1/2. CNP failed to alter GH3 cell proliferation or cell cycle distribution but caused a concentration-dependent increase in the activity of the human glycoprotein alpha-subunit promoter (alphaGSU) in a MEK-dependent manner. Finally, CNP also activated the p38 and JNK MAPK pathways in GH3 cells. These findings reveal an additional mechanism of GC-B signalling and suggest additional biological roles for CNP in its target tissues. FAU - Jonas, Kim C AU - Jonas KC AD - Endocrine Signalling Group, Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, 4 Royal College Street, London, NW1 0TU, UK. AD - Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 0TU, UK. FAU - Melrose, Timothy AU - Melrose T AD - Endocrine Signalling Group, Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, 4 Royal College Street, London, NW1 0TU, UK. AD - Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 0TU, UK. FAU - Thompson, Iain R AU - Thompson IR AD - Endocrine Signalling Group, Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, 4 Royal College Street, London, NW1 0TU, UK. AD - Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 0TU, UK. FAU - Baxter, Gary F AU - Baxter GF AD - Division of Pharmacology, The Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK. FAU - Lipscomb, Victoria J AU - Lipscomb VJ AD - Clinical Sciences & Services, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire, UK. FAU - Niessen, Stijn J AU - Niessen SJ AD - Clinical Sciences & Services, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire, UK. FAU - Lawson, Charlotte AU - Lawson C AD - Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 0TU, UK. FAU - McArdle, Craig A AU - McArdle CA AD - Laboratories for Integrative Neuroscience and Endocrinology, Department of Clinical Sciences at South Bristol, University of Bristol, Whitson Street, Bristol, BS13NY, UK. FAU - Roberson, Mark S AU - Roberson MS AD - Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. FAU - McGonnell, Imelda M AU - McGonnell IM AD - Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 0TU, UK. FAU - Wheeler-Jones, Caroline P AU - Wheeler-Jones CP AD - Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 0TU, UK. FAU - Fowkes, Robert C AU - Fowkes RC AD - Endocrine Signalling Group, Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, 4 Royal College Street, London, NW1 0TU, UK. rfowkes@rvc.ac.uk. AD - Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 0TU, UK. rfowkes@rvc.ac.uk. LA - eng GR - Wellcome Trust/United Kingdom GR - WT093257MA/Wellcome Trust/United Kingdom GR - BB/L002795/1/Biotechnology and Biological Sciences Research Council/United Kingdom GR - BBD0015601/Biotechnology and Biological Sciences Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170427 PL - Germany TA - Cell Tissue Res JT - Cell and tissue research JID - 0417625 RN - 127869-51-6 (Natriuretic Peptide, C-Type) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - EC 4.6.1.2 (Guanylate Cyclase) RN - EC 4.6.1.2 (Receptors, Guanylate Cyclase-Coupled) RN - H2D2X058MU (Cyclic GMP) SB - IM MH - Animals MH - Cell Line MH - Cyclic GMP/metabolism MH - Guanylate Cyclase/*metabolism MH - Humans MH - MAP Kinase Signaling System/*drug effects MH - Mitogen-Activated Protein Kinase Kinases/metabolism MH - Natriuretic Peptide, C-Type/*pharmacology MH - Phosphorylation/drug effects MH - Promoter Regions, Genetic/genetics MH - Receptors, Guanylate Cyclase-Coupled/metabolism MH - Somatotrophs/drug effects/*metabolism PMC - PMC5579180 OTO - NOTNLM OT - ERK1/2 OT - Guanylyl cyclase OT - Natriuretic OT - Pituitary OT - cGMP COIS- The authors have nothing to declare. EDAT- 2017/04/30 06:00 MHDA- 2018/12/26 06:00 PMCR- 2017/04/27 CRDT- 2017/04/29 06:00 PHST- 2017/02/02 00:00 [received] PHST- 2017/04/04 00:00 [accepted] PHST- 2017/04/30 06:00 [pubmed] PHST- 2018/12/26 06:00 [medline] PHST- 2017/04/29 06:00 [entrez] PHST- 2017/04/27 00:00 [pmc-release] AID - 10.1007/s00441-017-2624-x [pii] AID - 2624 [pii] AID - 10.1007/s00441-017-2624-x [doi] PST - ppublish SO - Cell Tissue Res. 2017 Sep;369(3):567-578. doi: 10.1007/s00441-017-2624-x. Epub 2017 Apr 27.