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    • br Funding This work was

    2021-10-15


    Funding This work was supported by the National Institutes of Health (RO1DK097550 to JT, RO1AG046619 to WAB and TS, and T32AG000057 to EMR, and T32DK007012 to SG) and by the Veterans Affairs Puget Sound Health Care System Research and Development.
    Introduction In mammals, two isoforms of growth hormone secretagogue-receptor (GHS-R) have been identified: functional receptor, GHS-R1a, and an alternative splice variant, GHS-R1b (Davenport et al., 2005). Ghrelin was discovered from the rat and human stomach as an endogenous ligand for the GHS-R1a (Kojima et al., 1999). Its third serine residue (Ser3) has an n-octanoyl modification at the side chain, and the acyl modification is known to be essential for eliciting ghrelin's activity. The widespread expression of GHS-R1a mRNA and translated protein from the central nervous system to various peripheral tissues supports the multiple actions of ghrelin such as growth hormone (GH) release, appetite regulation, glucose metabolism, cardiovascular function and gastrointestinal functions including motility and gastric Gefitinib secretion, and memory (Papotti et al., 2000, Gnanapavan et al., 2002, Kojima and Kangawa, 2005). Ghrelin is also present in the stomach or intestine of various non-mammalian vertebrates, and shows various functions (Kaiya et al., 2008, Kaiya et al., 2011b). Recently, we have concentrated on identification and characterization of the ghrelin receptor in non-mammalian vertebrates, and reported ghrelin receptors in two anuran amphibians, the bullfrog (Lithobates catesbeianus [Rana catesbeiana]) and the Japanese tree frog (Hyla japonica) (Kaiya et al., 2011a). In the study, we found interesting features: (i) the two frog GHS-R1a were capable of binding ghrelin, but both Ser3-ghrelin and Thr3-ghrelin increased intracellular Ca concentrations in a similar dose–response relationship even bullfrog and tree frog have Thr3-ghrelin and Ser3-ghrelin, respectively (Kaiya et al., 2001, Kaiya et al., 2011b); (ii) the identified frog GHS-R1a mRNA was not detected in the pituitary of both species (Kaiya et al., 2011a). This result was quite strange because bullfrog ghrelin is capable of stimulating growth hormone (GH) and prolactin (PRL) secretion from dispersed bullfrog pituitary cells (Kaiya et al., 2001). This result suggests that bullfrog and/or tree frog could have another type of GHS-R1a with different affinity between Ser3-ghrelin and Thr3-ghrelin in the pituitary. We recently determined an amphibian ghrelin other than frogs, which is in Japanese fire belly newt, Cynops pyrrhogaster, and it was Ser3-ghrelin (Kaiya et al., 2010). This suggests that a comparative study using newt may provide valuable information on ligand–receptor interaction of the ghrelin system including ligand selectivity of the receptor. The aim of this study is to isolate cDNA of functional ghrelin receptor in a urodele amphibian, the Japanese fire belly newt. We examined functionality of the identified receptor and ligand selectivity, as well as tissue distribution of its mRNA. In addition, we examined possible involvement of the ghrelin system in energy metabolism in this newt by food deprivation experiment for 2weeks.
    Materials and methods
    Results
    Discussion Recently we identified and characterized the ghrelin receptor in two anuran amphibians, bullfrog and Japanese tree frog (Kaiya et al., 2011a). This was a follow-up study to look at the structure and possible difference of the characteristics of the ghrelin receptor in urodele amphibian. Sequence alignment and phylogenetic analysis clearly supported that the identified newt protein is the ghrelin receptor. The ghrelin receptor is roughly divided into two types, which are GHS-Ra and GHS-R1a-like receptor. GHS-Ra is further divided into two: GHS-R1a and 2a (Kaiya et al., 2013a, Kaiya et al., 2013b, Kaiya et al., 2014). These are paralogous relationship with 67–74% sequence identities between the two, and it is considered to be generated by the second-round of whole genome duplication (2R WGD) or fish-specific 3R WGD (Meyer and Van de Peer, 2005). GHS-R2a is a relatively newly identified ghrelin receptor, and was found in some teleost species such as zebrafish, channel catfish and goldfish (Kaiya et al., 2008, Kaiya et al., 2010, Small et al., 2009). On the other hand, GHS-R1a-like receptor (GHS-R1a-LR) is considered to be another sub-group of the ghrelin receptor that is only found in physoclistian teleosts (Palyha et al., 2000, Chen and Cheng, 2004, Kaiya et al., 2009a, Kaiya et al., 2009b, Kaiya et al., 2014). Tetrapod ghrelin receptor is GHS-R1a without any exception including newts.