Abstract
The evolutionary trajectories of growth hormone-releasing hormone (GHRH) receptor remain enigmatic since the discovery of physiologically functional GHRH-GHRH receptor (GHRHR) in non-mammalian vertebrates in 2007. Interestingly, subsequent studies have described the identification of a GHRHR2 in chicken in addition to the GHRHR and the closely related paralogous receptor, PACAP-related peptide (PRP) receptor (PRPR). In this article, we provide information, for the first time, on the GHRHR in sarcopterygian fish and amphibians by the cloning and characterization of GHRHRs from lungfish (P. dolloi ) and X. laevis. Sequence alignment and phylogenetic analyses demonstrated structural resemblance of lungfish GHRHR to their mammalian orthologs, while the X. laevis GHRHR showed the highest homology to GHRHR2 in zebrafish and chicken. Functionally, lungfish GHRHR displayed high affinity towards GHRH in triggering intracellular cAMP and calcium accumulation, while X. laevis GHRHR2 was able to react with both endogenous GHRH and PRP. Tissue distribution analyses showed that both lungfish GHRHR and X. laevis GHRHR2 had the highest expression in brain, and interestingly, X. laevis GHRHR2 also had high abundance in the reproductive organs. These findings, together with previous reports, suggest that early in the Sarcopterygii lineage, GHRHR and PRPR have already established diverged and specific affinities towards their cognate ligands. GHRHR2, which has only been found in xenopus, zebrafish and chicken hitherto, accommodates both GHRH and PRP.
Highlights
Growth hormone-releasing hormone receptor (GHRHR) is a specific receptor for the growth hormone-releasing hormone (GHRH) in mammals which controls the synthesis and release of growth hormone (GH) from the anterior pituitary somatotrophs
GHRHR belongs to the seven transmembrane secretin Gprotein coupled receptor (GPCR) family, which includes the receptors of secretin, glucagon, pituitary adenylate cyclase activating poplypeptide (PACAP), PACAP-related peptide (PRP), vasoactive intestinal peptide (VIP), parathyroid hormone (PTH) and calcitonin [7]
Does Lungfish GHRHR have an Endogenous Ligand? Substantiated by the sequence alignment and phylogenetic analyses, lungfish GHRHR (lfGHRHR) is showing a structural similarity to the mammalian GHRHRs
Summary
Growth hormone-releasing hormone receptor (GHRHR) is a specific receptor for the growth hormone-releasing hormone (GHRH) in mammals which controls the synthesis and release of growth hormone (GH) from the anterior pituitary somatotrophs. Cloned from human, rat, and mouse pituitary, the isolated cDNA was found to encode a 423-amino acid protein with highly conserved sequence identities [1,2,3]. In 2007, our group discovered a novel GHRHGHRHR axis in teleosts (zebrafish and goldfish), showing that a ‘‘true’’ GHRH-GHRHR which is capable of stimulating GH secretion exists, while the GHRH-like ligand-receptor pair is orthologs of vertebrate PRP-PRPR [9]. In chicken G. gallus, a second GHRHR gene (GHRHR2) was found, it only shared 46% amino acid sequence identity to the first GHRHR. A gene orthologous to the chicken GHRHR2 was identified in X. tropicalis and zebrafish genomes, but not in mouse, rat and human [12]
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