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

Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas 77030

Address all correspondence and requests for reprints to: Carmen W. Dessauer, Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, Texas 77030. E-mail: Carmen.W.Dessauer{at}uth.tmc.edu.

Relaxin is a polypeptide hormone that activates the leucine-rich repeat containing 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 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 (PKC) 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. Chelerythrine chloride (a general PKC inhibitor) inhibits relaxin induced cAMP production to the same degree (40%) as LY294002. Relaxin stimulates PKC translocation to the plasma membrane in THP-1, MCF-7, pregnant human myometrial 1–31, and mouse mesangial cells, as shown by immunocytochemistry. PKC translocation is phosphoinositide-3 kinase dependent and independent of cAMP production. Antisense PKC oligodeoxynucleotides (PKC-ODNs) deplete both PKC transcript and protein levels in THP-1 cells. PKC-ODNs abolish relaxin-mediated PKC 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-ODNs results in little further inhibition. In summary, we present a novel role for PKC in relaxin-mediated stimulation of cAMP.

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