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 ORCID: https://orcid.org/0000-0002-7887-6841, 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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Abstract

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:	11 Oct 2023 17:41
URI:	https://orca.cardiff.ac.uk/id/eprint/100731

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