PMID:16569707

Citation	Halls, ML, Bathgate, RA and Summers, RJ (2006) Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms. Mol. Pharmacol. 70:214-26
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 (INSL) 3. Human gene 2 relaxin is the cognate ligand for relaxin family peptide receptor (RXFP) 1, whereas INSL3 is the ligand for RXFP2. Constitutively active mutants of both receptors when expressed in human embryonic kidney (HEK) 293T cells signal through Galphas to increase cAMP. However, recent studies using cells that endogenously express the receptors revealed greater complexity: cAMP accumulation after activation of RXFP1 involves a time-dependent biphasic pathway with a delayed phase involving phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC) zeta, whereas the RXFP2 response involves inhibition of adenylate cyclase via pertussis toxin-sensitive G proteins. The aim of this study was to compare and contrast the cAMP signaling pathways used by these two related receptors. In HEK293T cells stably transfected with RXFP1, preliminary studies confirmed the biphasic cAMP response, with an initial Galphas component and a delayed response involving PI3K and PKCzeta. This delayed pathway was dependent upon G-betagamma subunits derived from Galphai3. An additional inhibitory pathway involving GalphaoB affecting cAMP accumulation was also identified. In HEK293T cells stably transfected with RXFP2, the cAMP response involved Galphas and was modulated by inhibition mediated by GalphaoB and release of inhibitory G-betagamma subunits. Thus, initially both RXFP1 and RXFP2 couple to Galphas and an inhibitory GalphaoB pathway. Differences in cAMP accumulation stem from the ability of RXFP1 to recruit coupling to Galphai3, release G-betagamma subunits and thus activate a delayed PI3K-PKCzeta pathway to further increase cAMP accumulation.
Links	PubMed Online version:10.1124/mol.105.021691
Keywords	Alkaloids; Androstadienes/pharmacology; Benzophenanthridines; Cell Line; Cyclic AMP/metabolism; Dose-Response Relationship, Drug; GTP-Binding Proteins/genetics; GTP-Binding Proteins/metabolism; Humans; Insulin/pharmacology; Pertussis Toxin/pharmacology; Phenanthridines/pharmacology; Phosphatidylinositol 3-Kinases/antagonists & inhibitors; Phosphatidylinositol 3-Kinases/metabolism; Protein Isoforms/genetics; Protein Isoforms/physiology; Protein Kinase C/antagonists & inhibitors; Protein Kinase C/metabolism; Proteins/pharmacology; Receptors, G-Protein-Coupled/genetics; Receptors, G-Protein-Coupled/physiology; Receptors, Peptide/genetics; Receptors, Peptide/physiology; Relaxin/pharmacology; Signal Transduction/drug effects; Signal Transduction/physiology; Time Factors; Transfection
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:RXFP1		GO:0030819 : positive regulation of cAMP biosynthetic process	ECO:0000314:		P		In figure 1, the authors demonstrate that human RXFP1 has a positive influence on cAMP production in the presence of its ligand.	complete CACAO 1964

References

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