Mechanisms of relaxin receptor (LGR7/RXFP1) expression and function.
The LGR7/RXFP1 and LGR8/RXFP2 receptors are unique receptors among the G-protein-coupled receptors (GPCRs) in having a low-density lipoprotein class A (LDL-A) module. Their complex gene organization, among the intron-richest of the GPCRs, suggests that alternative splicing is a common occurrence. We have therefore investigated the role of the LDL-A module and shown the identity, expression, and functions of three LGR7 splice variants in the human decidua. Point mutations of conserved residues or complete deletion of the LDL-A module resulted in loss of the cAMP response to relaxin. Its glycosylation also impacted LGR7 cell surface delivery and therefore receptor activation. The wild-type (WT) LGR7 was expressed as both precursor and mature forms, but deletion of the LDL-A module resulted in expression of only the mature form. Three new alternatively spliced variants of LGR7 were identified, all containing a truncated extracellular region. Their functional characterization showed them exerting dominant negative effects on the WT LGR7 by preventing its homodimerization, maturation, and subsequent trafficking to the cell surface, resulting in loss of function. In summary, different mechanisms have been identified for controlling the cell surface expression and function of the LGR7 protein which are likely to be significant for the role of relaxin in human parturition.
Kern
András
A
The Pacific Biosciences Research Center, University of Hawaii, Honolulu, Hawaii 96822, USA. kerna@pbrc.hawaii.edu
Bryant-Greenwood
Gillian D
GD
D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D017354:Point Mutation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012065:Relaxin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
C417543:RXFP1 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D012065:Relaxin; D000242:Cyclic AMP