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Natriuretic peptide activation of extracellular regulated kinase 1/2 (ERK1/2) pathway by particulate guanylyl cyclases in GH3 somatolactotropes

Jonas, Kim C., Melrose, Timothy, Thompson, Iain R., Baxter, Gary Francis, Lipscomb, Victoria J., Niessen, Stijn J., Lawson, Charlotte, McArdle, Craig A., Roberson, Mark S., McGonnell, Imelda M., Wheeler-Jones, Caroline P. and Fowkes, Robert C. 2017. Natriuretic peptide activation of extracellular regulated kinase 1/2 (ERK1/2) pathway by particulate guanylyl cyclases in GH3 somatolactotropes. Cell and Tissue Research 369 (3) , pp. 567-578. 10.1007/s00441-017-2624-x

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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 α-subunit promoter (αGSU) 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Uncontrolled Keywords: Natriuretic, cGMP, Guanylyl cyclase, Pituitary, ERK1/2
Publisher: Springer Verlag
ISSN: 0302-766X
Date of First Compliant Deposit: 22 May 2017
Date of Acceptance: 4 April 2017
Last Modified: 10 Jan 2018 17:21

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