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This version published online on December 16, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0279
A more recent version of this article appeared on April 1, 2005
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Submitted on July 8, 2004
Accepted on December 8, 2004

Relaxin Stimulates Protein Kinase C Zeta Translocation: Requirement for Cyclic Adenosine 3',5'-Monophosphate Production

Bao T. Nguyen and Carmen W. Dessauer*

Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030. Tel: (713) 500-6308, Fax: (713) 500-7444, E-mail: Carmen.W.Dessauer@uth.tmc.edu

* To whom correspondence should be addressed. E-mail: Carmen.W.Dessauer{at}uth.tmc.edu.

Relaxin is a polypeptide hormone that activates the G protein-coupled receptors, LGR7 and LGR8. In an earlier study, we reported that relaxin produces a biphasic time course and the second wave of cAMP is highly sensitive to phosphoinositide-3 kinase (PI3K) inhibitors (LY294002 and wortmannin). LY294002 inhibits relaxin-mediated increases in cAMP production by 40-50% across a large range of relaxin concentrations. Here we show that protein kinase C zeta (PKC{zeta}) is a component of relaxin signaling in THP-1 cells. Sphingomyelinase increases cAMP production due to the release of ceramide, a direct activator of PKC{zeta}. Chelerythrine chloride (a general PKC inhibitor) inhibits relaxin induced cAMP production to the same degree (~ 40%) as LY294002. Relaxin stimulates PKC{zeta} translocation to the plasma membrane in THP-1, MCF-7, PHM1-31, and MMC cells, as shown by immunocytochemistry. PKC{zeta} translocation is PI3K-dependent and independent of cAMP production. Antisense PKC{zeta} oligodeoxynucleotides (PKC{zeta}-ODNs) deplete both PKC{zeta} transcript and protein levels in THP-1 cells. PKC{zeta}-ODNs abolish relaxin-mediated PKC{zeta} translocation and inhibit relaxin stimulation of cAMP by 40%, as compared with mock and random ODN controls. Treatment with LY294002 in the presence of PKC{zeta}-ODNs results in little further inhibition. In summary, we present a novel role for PKC{zeta} in relaxin-mediated stimulation of cAMP.
Key words: Relaxin • adenylyl cyclase • G protein • protein kinase C zeta • phosphoinositide 3-kinase • LGR7 • LGR8 • THP-1 cells




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