Received for publication December 15, 2005.
Revised March 27, 2006.
Accepted for publication March 28, 2006.

Relaxin family peptide receptors, RXFP1 and RXFP2, modulate cAMP signalling by distinct mechanisms

Abstract

Two orphan leucine-rich repeat-containing G protein-coupled receptors were recently identified as targets for the relaxin family peptides relaxin and insulin-like peptide 3 (INSL3). Human gene 2 (H2) relaxin is the cognate ligand for relaxin family peptide receptor 1 (RXFP1), while INSL3 is the ligand for RXFP2. Constitutively active mutants of both receptors when expressed in HEK293T cells signal through G_s to increase cAMP. However, recent studies utilizing cells that endogenously express the receptors revealed greater complexity: cAMP accumulation following activation of RXFP1 involves a time-dependent biphasic pathway with a delayed phase involving PI3K and PKC, whereas the RXFP2 response involves inhibition of adenylate cyclase via PTX-sensitive G proteins. The aim of this study was to compare and contrast the cAMP signalling pathways utilized by these two related receptors. In HEK293T cells stably transfected with RXFP1, preliminary studies confirmed the biphasic cAMP response, with an initial G_s component and a delayed response involving PI3K and PKC. This delayed pathway was dependent upon G- subunits derived from G_i3. An additional inhibitory pathway involving G_oB affecting cAMP accumulation was also identified. In HEK293T cells stably transfected with RXFP2 the cAMP response involved G_s and was modulated by inhibition mediated by G_oB and release of inhibitory G- subunits. Thus initially both RXFP1 and RXFP2 couple to G_s and an inhibitory G_oB pathway. Differences in cAMP accumulation stem from the ability of RXFP1 to recruit coupling to G_i3, release G- subunits and thus activate a delayed PI3K-PKC pathway to further increase cAMP accumulation.

Key words: Orphan, Gi family, Gs family, cAMP, Mutagenesis/Chimeric approaches

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