RXFP1 couples to the Galpha-Gbetagamma-PI3K-PKCzeta pathway via the final 10 amino acids of the receptor C-terminal tail.
The relaxin family peptide receptors RXFP1 and RXFP2 are highly similar receptors that share approximately 80% amino acid sequence homology. Constitutively active receptors couple to increased cAMP accumulation, which is important for relaxin-mediated decidualization and myometrial inhibition. Despite the high homology, the receptors couple to different G-proteins to affect cAMP accumulation. This study aimed to determine the region of RXFP1 that directs coupling to the delayed Galpha(i3) pathway by using receptor mutagenesis. Receptor chimeras suggested that activation of this pathway by RXFP1 was dependent upon the membrane-anchored domain of the receptor. Further receptor mutagenesis showed that activation of the Galpha(i3)-Gbetagamma-PI3K-PKCzeta cAMP pathway by RXFP1 is dependent upon the C-terminal 10 amino acids of the receptor and absolutely requires Arg(752).
Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
Michelle L
ML
Halls
Maria
M
Papaioannou
John D
JD
Wade
Bronwyn A
BA
Evans
Ross A D
RA
Bathgate
Roger J
RJ
Summers
D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D006801:Humans; D016296:Mutagenesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship
C118981:G-protein Beta gamma; D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; C417543:RXFP1 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases