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,1
* School of Life Sciences, Sichuan University, Chengdu, 610064, P. R. China; and School of Biological Sciences, The University of Hong Kong, China
1 Corresponding authors: lijuanhk{at}gmail.com and fcleung{at}hkucc.hku.hk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: chicken • glucagon • glucagon receptor • glucagon receptor variant
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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cells of islets of Langer-hans in response to low glucose levels, whereas GLP-1 and GLP-2, but not glucagon, are produced in intestinal L cells and central nervous system (CNS) (Mojsov et al., 1986; Drucker and Asa, 1988; Furuta et al., 2001; Mayo et al., 2003). A large body of evidence shows that glucagon can enhance hepatic glucose output through increasing glycogenolysis and gluconeogenesis in liver and thus effectively counteract the glucose-lowering effect of insulin (Jiang and Zhang, 2003). Similar to observations in mammals, glucagon increases hepatic glucose production in birds and fish (Langslow and Siddle, 1979; Sugano et al., 1982; Plisetskaya and Mommsen, 1996; Chow et al., 2004), suggesting a conserved role of glucagon during vertebrate evolution. In addition to its action in liver, glucagon has been reported to have important roles in the mammalian nonhepatic tissues such as stimulating inotropic activity in the heart, controlling ion transport and electrolyte excretion in the kidney (Brubaker and Drucker, 2002), and inhibiting food intake and stimulating hypothalamic somatostatin release in the CNS (Shimatsu et al., 1983; Inokuchi et al., 1984). In mammals, the biological actions of glucagon are mediated by a specific glucagon receptor (GCGR; Authier and Desbuquois, 2008; Brubaker and Drucker, 2002), a receptor belonging to G protein-coupled receptor subfamily B, which also includes the receptors for GLP-1, GLP-2, vasoactive intestinal polypeptide, growth hormone-releasing hormone (GHRH), and growth hormone-releasing hormone-like peptide (Sherwood et al., 2000; Mayo et al., 2003). Activation of glucagon receptor can trigger intracellular cyclic adenosine monophosphate (cAMP) accumulation and [Ca2+] mobilization, and consequently lead to target gene transcription (Jelinek et al., 1993; Authier and Desbuquois, 2008). Targeted disruption of mouse glucagon receptor gene can abolish glucagon binding and glucagon-induced cAMP production in liver membranes in vitro and also reduce blood glucose levels in vivo under both fasting and fed states, clearly suggesting the critical role of a specific glucagon receptor in mediating biological actions of glucagon (Plisetskaya and Mommsen, 1996; Parker et al., 2002; Gelling et al., 2003). As in mammals, the receptor specific for glucagon has been cloned and characterized in frog (Ngan et al., 1999; Sivarajah et al., 2001) and goldfish (Chow et al., 2004). However, glucagon receptor has not yet been cloned and characterized in any avian species.
Although glucagon has been shown to stimulate hepatic glucose production in fish, GLP-1 appears to be more potent than glucagon in most fish, which is different from that reported in mammals (Mommsen et al., 1987; Plisetskaya and Mommsen, 1996; Mojsov, 2000; Mommsen, 2000). The dramatic functional switch of the 2 closely related (structurally) peptides between fish and mammals, therefore, requires further study to uncover the underlying molecular mechanisms in different classes of vertebrates including birds. Using the chicken as an experimental model, the present study aimed to clone the glucagon receptor and characterize its functionality, and then investigate its expression in hepatic and nonhepatic tissues. The results from this study will not only establish a molecular basis for better understanding of the physiological roles of glucagon in chicken, but also shed light on the structural and functional changes of glucagon and its receptor in the course of vertebrate evolution.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All chemicals were obtained from Sigma-Aldrich (St. Louis, MO), and restriction enzymes were obtained from Amersham Biosciences (GE Healthcare Bio-Sciences Corp., Piscataway, NJ) unless stated otherwise. Human glucagon1–29 was purchased from Bachem (Bachem Inc., Torrance, CA). Chicken vasoactive intestinal polypeptide (cVIP) was a gift from M. E. El-Halawani (Department of Animal Science, University of Minnesota, St. Paul). Chicken GHRH1–47 (cGHRH1–47) and GHRH-like peptide (cGHRH-LP1–46) were synthesized using solid-phase Fmoc chemistry (GL Biochem, Shanghai, China). The purity of synthesized chicken peptides was greater than 95% (analyzed by HPLC) and their structure was verified by mass spectrometry (GL Biochem). Human glucagon was dissolved in 0.1 N HCl, and cGHRH1–47, cGHRH-LP1–46, and cVIP were dissolved in distilled water, and then diluted to the desired concentrations with medium before use.
Total RNA Extraction
Adult chickens were killed and different tissues including small intestine, heart, kidney, liver, lung, muscle, ovary, pituitary, spleen, pancreas, testis, spinal cord, and whole brain (or different brain regions including telencephalon, cerebellum, hindbrain, midbrain, and hypothalamus) were collected for total RNA extraction. Total RNA was extracted from chicken tissues by using Tri-reagent (Molecular Research Center, Cincinnati, OH) according to the manufacturer’s instructions and dissolved in diethyl pyrocarbonate (DEPC)-treated H2O. All experiments were performed under license from the Government of the Hong Kong Special Administrative Region and endorsed by the Animal Experimentation Ethics Committee of The University of Hong Kong.
Cloning the Full-Length cDNA for Chicken Glucagon Receptor
To obtain the full-length cDNA of glucagon receptor, 2 gene-specific primers flanking the start and stop codons (with a restriction enzyme recognition site added at the 5' end) were designed (Table 1
) based on the information from chicken genome database (http://www.emsembl.org/Gallus_gallus), and EST sequences deposited in GenBank (accession nos.: BM426472
[GenBank]
, BM427510
[GenBank]
, and BX271916
[GenBank]
; Carre et al., 2006). The full-length cDNA of glucagon receptor were amplified from adult chicken brain using high-fidelity Taq DNA polymerase (Roche Diagnostics, Basel, Switzerland). The PCR products were cloned into pBluescript II SK (+/–) (Stratagene, La Jolla, CA). The full-length cDNA were finally determined by sequencing (Perkin-Elmer, Foster City, CA) at least 3 independent clones containing whole open reading frames.
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Reverse transcription (RT) was performed at 42°C for 2 h in a total volume of 10 µL consisting of 2 µg of total RNA from different tissues, 1 x single strand buffer, 0.5 mM each deoxynucleotide triphosphate, 0.5 µg of oligodeoxythymide, and 100 U of Moloney murine leukemia virus reverse transcriptase (Promega, Madison, WI). All negative controls were carried out under the same conditions without reverse transcriptase added in the 10 µL of reaction mix.
One microliter of the first-strand cDNA was used as the template for each PCR reaction. According to our previously established methods (Wang et al., 2003; Wang and Ge, 2004; Wang et al., 2007b), RT-PCR assays were performed to examine the relative mRNA levels of glucagon receptor in chicken tissues. The PCR was performed under the following conditions: 2 min at 95°C for denaturation, followed by 23 cycles (for β-actin: 30 s at 95°C, 30 s at 58°C, and 60 s at 72°C) and 29 (or 35) cycles (for glucagon receptor: 30 s at 95°C, 30 s at 58°C, 60 s at 72°C) of reaction, ending with a 5-min extension at 72°C. The primers used for glucagon receptor gene and β-actin gene are listed in Table 1
. The PCR products were visualized on an ultraviolet transilluminator (Bio-Rad Laboratories, Hercules, CA) after electrophoresis on a 2% agarose gel containing ethidium bromide.
Functional Characterization of Chicken Glucagon Receptor
The pBluescript SK (+/–) plasmid containing the full-length glucagon receptor was first released by restriction enzyme digestion (HindIII and EcoRI) and then subcloned into the pcDNA3.1 (+) expression vector (Invitrogen, Carlsbad, CA). To test the functionality of chicken glucagon receptor, the pGL3-CRE-luciferase reporter construct was used in this study (Wang et al., 2007c). The pGL3-CRE-luciferase reporter plasmid was constructed by inserting a promoter containing multiple cAMP-response elements into the promoter-less pGL3-Basic vector (Promega; Wang et al., 2007c). The Chinese hamster ovary (CHO) cells were cultured in Dulbecco’s modified Eagle’s medium supplemented with 10% (vol/vol) fetal bovine serum (HyClone Logan, UT), 100 U/mL of penicillin G, and 100 µg/mL of streptomycin (Life Technologies Inc., Grand Island, NY) in a 90-cm culture dish (Nunc, Rochester, NY) and incubated at 37°C with 5% CO2. Cells were then plated in a 6-well plate at a density of 3 x 105 cells per well 1 d before transfection. A mixture containing 700 ng of pGL3-CRE-luciferase reporter construct, 200 ng of pcDNA3.1 expression plasmids encoding glucagon receptor (or empty vector), and 6 µL of Lipofectamine (Invitrogen) was prepared in 50 µL of PBS. Transfection was performed according to the manufacturer’s instructions when cells reached 70% confluency. After 24 h of culture, the CHO cells were trypsinized and cultured in a 96-well plate at a density of 2 x 104 cells per well at 37°C for 24h before hormone treatment. After removal of medium from 96-well plate, 100 µL of hormone-containing medium was added. The cells were incubated for an additional 6 h at 37°C before being harvested for luciferase assay. After removal of culture medium, CHO cells were lysed by adding 50 µL of 1 x passive lysis buffer (Promega) per well, and the luciferase activity of 15 µL of cellular lysates was determined using luciferase assay reagent (Promega).
Data Analysis
The luciferase activities in each treatment group were expressed as relative fold increase compared with the control group (without hormone treatment). The data were analyzed by one-way ANOVA followed by Dunnett’s test using GraphPad Prism 4 (GraphPad Software, San Diego, CA). To validate our results, all experiments were repeated at least 2 times.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Based on the information from chicken genome database and several EST sequences (accession nos. BM426472
[GenBank]
, BM427510
[GenBank]
, and BX271916
[GenBank]
; Carre et al., 2006), 2 gene-specific primers were designed to amplify the full-length cDNA of chicken glucagon receptor in this study. As a result, a full-length cDNA of glucagon receptor (1,512 bp) was successfully cloned from adult chicken brain tissue (accession no. EF624352
[GenBank]
). It encodes a glucagon receptor precursor of 496 AA (Figure 1). Similar to GCGR of other species, chicken GCGR also contains a large N-terminal extracellular domain, 7 transmembrane domains (TMD), and a long carboxyl terminus (Unson, 2002; Authier and Desbuquois, 2008). Moreover, 4 putative N-linked glycosylation sites (N-X-S or N-X-T, where X represents any AA except proline) are also found in the large extracellular domain (Figure 2). Alignment of chicken GCGR with other species shows that chicken GCGR shares high AA sequence identity with that of human (70%; MacNeil et al., 1994), rat (69%; Jelinek et al., 1993), mouse (69%; Burcelin et al., 1995), Xenopus (64%; Sivarajah et al., 2001), and a comparatively lower identity to goldfish (53%; Chow et al., 2004), with the greatest degree of identity observed in the 7 TMD. In addition, 6 cysteine residues critical for the formation of 3 intramolecular disulfide bonds in the extracellular domain, together with the Arg-Leu-Ala-Lys (RLAK) motif responsible for G-protein coupling in the third intracellular loop, are strictly positioned and conserved among all species (Unson, 2002). In contrast, the long C-terminal tails vary in length and show significant variability (Figure 2).
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and 2). Comparison of this new cDNA with the chicken genome database (http://www.emsembl.org/Gallus_gallus) revealed that this 174-bp sequence corresponds to intron 4 of chicken GCGR. To verify that this transcript variant was not an artifact of PCR amplification, we designed another set of primers to amplify this region (Table 1). Again, this variant could be amplified from chicken liver tissue and its identity was confirmed by sequencing (Figure 1). Moreover, the existence of this receptor variant was further supported by an EST deposited in GenBank (accession no. BI066276.1; Carre et al., 2006).
There are, therefore, 2 forms of GCGR identified in chickens: the short glucagon receptor of 496 AA (GCGR-s) and the long receptor variant of 554 AA, designated glucagon receptor variant 1 (GCGR-v1) in this study (Figures 1 and 2).
Functional Characterization of Chicken GCGR-s and GCGR-v1
Because glucagon has been shown to be capable of increasing adenylate cyclase activity and cAMP levels of isolated chicken hepatocytes (Langslow and Siddle, 1979; Premont and Iyengar, 1988), it led us to examine whether the cloned chicken glucagon receptor could be activated by glucagon and functionally coupled to the cAMP-protein kinase A (PKA) signaling pathway. To address this issue, chicken GCGR-s was expressed in vitro and subjected to treatment with human glucagon and other peptides from the glucagon/secretin family, including cVIP, cGHRH1–47, and cGHRH-LP1–46 (Campbell and Scanes, 1992; Sherwood et al., 2000) As expected, human glucagon, but not the other peptides tested, could stimulate luciferase activity in a dose-dependent manner via activation of chicken GCGR-s [half maximal effective concentration (EC50) = 1.17 nM], confirming that GCGR-s is functional and able to couple to the cAMP-PKA signaling pathway. In contrast, no change in luciferase activity was observed in internal controls, which were conducted by cotransfection of empty pcDNA3.1 vector and pGL3-CRE-luciferase construct into CHO cells (Figure 3).
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Tissue Distribution of Chicken Glucagon Receptor mRNA
To elucidate the roles of glucagon in target tissues, we further examined the expression of glucagon receptor in various adult chicken tissues using RT-PCR. Using a large number of PCR cycles (35), the strongest PCR signal was consistently detected in the livers of different individuals, whereas moderate or weak signals were noted in the other 11 tissues including whole brain, heart, small intestine, kidney, lung, muscle, ovary, pituitary, spleen, testis, and pancreas. When fewer PCR cycles (29) were used, the strong signal could still be detected in liver, whereas weak or no signal was detected in other tissues, confirming that glucagon receptor is highly expressed in liver (Figure 4A).
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).
To evaluate the relative expression levels of GCGR-s and GCGR-v1 in chicken tissues, we used another set of primers to amplify both GCGR-s and GCGR-v1 (Table 1). Because the amplified region is GC-rich (~70%), effective PCR detection in tissues with low levels of glucagon receptor expression is difficult. However, a weak PCR signal for GCGR-v1 and a strong signal for GCGR-s were noted in several tissues including liver, telencephalon, and hypothalamus, suggesting predominant expression of GCGR-s in these tissues (Figure 4). In parallel with the above experiments, negative controls were performed in each RT-PCR assay and no band was observed (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although the cloned chicken GCGR (GCGR-s) shares approximately 70% AA identity to those of mammalian species and relatively low identity to that in goldfish (53%), the phylogenetic tree constructed by the neighbor-joining method using MEGA3.1 (Kumar et al., 2004) still supports that chicken GCGR and GCGR from other species are grouped into a monophyletic cluster (Figure 5). Interestingly, goldfish GLP-1 receptor (GLP1R) falls into the same cluster, and the reliability of this tree topology is substantiated by the high bootstrap values (Figure 5). In sharp contrast, GLP1R from chicken, rat, human, and mouse are grouped into another monophyletic cluster (Figure 5). One possible explanation for this inconsistency is that goldfish GCGR and GLP1R may have originated from an early gene (gcgr) duplication event in the fish lineage as proposed by Irwin (2005), and thus shared a closer evolutionary relationship (Irwin, 2005; Irwin and Wong, 2005). The identification of a fish GLP1R gene orthologous to the mammalian or chicken GLP1R gene would provide interesting clues to this hypothesis.
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). Similar to other members from G protein-coupled receptor subfamily B, an aspartate at position 58 and 6 cysteines in the large N-terminal domain are strictly positioned and conserved (Carruthers et al., 1994; Unson et al., 1995; Unson, 2002; Mayo et al., 2003; Wang et al., 2007a). This remarkable degree of conservation is consistent with the concept that these domains and residues are critical for proper receptor folding, cell surface targeting, and high-affinity ligand binding (Carruthers et al., 1994; Unson, 2002). It was reported that N-linked glycosylation of rat glucagon receptor may not be required for intracellular trafficking, protein folding, and ligand binding (Unson et al., 1995), 3 of the 4 N-linked glycoslyation sites found in chicken GCGR-s are well preserved in all species, suggesting a common role of N-linked glycosylation in receptor function. In contrast to the conservation of TMD and N-terminal extracellular domains, the C-terminal tails vary in length and show significant diversity across species (Figure 2). Although several residues, such as serines, within the long C-termini distal to seventh TMD of human GCGR have been shown to be critical for receptor internalization and desensitization (Buggy et al., 1997), the low homology within this region suggests that other residues may also be involved in this process. In contrast, the C-terminal region near the seventh TMD is highly conserved, emphasizing its roles in receptor function (Unson et al., 1995; Buggy et al., 1997). Indeed, this notion has been substantiated by truncated rat and human GCGR sequences (Unson et al., 1995; Buggy et al., 1997). Deletion of the C-terminal part distal to TMD 7 does not impair receptor binding, activation, and signaling, whereas deletion of the whole C-terminal tail will render the receptor completely defective in signaling and ligand binding (Unson et al., 1995). Thus, the conservation of critical domains, motifs, and residues between chicken and other GCGR sequences supports the hypothesis that chicken GCGR-s is likely a functional receptor.
In addition to the cloned GCGR-s, we have also identified a novel full-length cDNA encoding a GCGR variant of 554 AA. Sequence analysis confirmed that it resulted from retention of intron 4 (174 bp) and hence, caused an insertion of additional 58 AA at the large N-terminal extracellular domain. Although a full-length GCGR variant has not been reported in any vertebrate species, a partial GCGR cDNA with retention of intron 4 (81 bp) was also found to be expressed in rat liver (Maget et al., 1994). The identical splicing pattern of GCGR between chickens and rats points to the possibility that GCGR variant may be expressed in mammalian tissues as noted in this study (Figures 1 and 2).
The considerable degree of sequence diversity of GCGR across species led us to examine the functionality of chicken GCGR-s. As expected, human glucagon stimulated luciferase activity of CHO cells via activation of GCGR-s in a dose-dependent manner, suggesting that chicken GCGR-s, like GCGR from other species, is able to couple to the intracellular cAMP-PKA signaling pathway (Langslow and Siddle, 1979; Brubaker and Drucker, 2002). In contrast, the structurally related peptides cVIP, cGHRH, and cGHRH-LP fail to stimulate luciferase activity at any dosage tested. This finding suggests that glucagon is an endogenous ligand of chicken GCGR-s. It has been reported that GCGR can be activated by glucagon-like peptide 1 at high dosages in teleost fish (Chow et al., 2004). Because chicken GLP-1 is not available in our laboratory, we cannot verify whether GLP-1 could activate chicken GCGR-s potently. Despite this uncertainty, the activation of chicken GCGR-s by glucagon at concentrations less than 1 nM strongly suggests that chicken GCGR-s could mediate the actions of glucagon under physiological conditions.
The identification of GCGR-v1 in chickens led us to investigate its functionality. Interestingly, insertion of 58 AA in the large N-terminal extracellular domain of chicken GCGR does not impair receptor function and coupling to the cAMP-PKA pathway. In contrast, human glucagon appears to activate GCGR-v1 more potently than chicken GCGR-s. This finding is interesting but not surprising. Similar to cGCGR-v1, at the same location, mammalian and chicken pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1-Rs) also has an insertion of 21 or 26 AA (Pantaloni et al., 1996; Dautzenberg et al., 1999), which shows low homology between chicken and mammals. The presence of these extra AA does not affect receptor activation, but it makes human PAC1-Rs preferentially bind PACAP, but not vasoactive intestinal polypeptide (Dautzenberg et al., 1999). Our data, together with these findings in mammals (Dautzenberg et al., 1999), lead us to speculate that the insertion of chicken GCGR-v1 may change the binding affinity to certain ligand(s). However, this idea needs further verification.
As a primary action site of glucagon in vertebrates, chicken liver also has the greatest expression level of GCGR compared with other tissues (Figure 4). This finding is consistent with the abundant expression of GCGR in rat and mouse liver (Burcelin et al., 1995; Dunphy et al., 1998), suggesting a conserved role of glucagon in hepatic tissues of vertebrates. In addition to its expression in liver, chicken GCGR is widely expressed in all other tissues examined. While we were preparing this article, Richards and McMurtry (2008) reported that GCGR mRNA is widely expressed in all tissues examined in 3-wk-old male chicks. These consistent findings suggest that glucagon plays a range of roles in both hepatic and nonhepatic tissues of chicken (Richards and McMurtry, 2008). In the CNS, expression of GCGR was detected in all brain regions with the greatest expression being detected in the hypothalamus, suggesting that hypothalamus may be a major action site of glucagon. This hypothesis is supported by the report that intracerebroventricular infusion of glucagon can strongly inhibit food intake (Honda et al., 2007). At this stage, we have yet to determine where glucagon is produced in the CNS, but the detection of glucagon mRNA expression in chicken brain provides the possibility that glucagon may be synthesized locally (Richards and McMurtry, 2008). Despite the fact that posttranslational processing of glucagon precursor may preferentially produce other peptides such as GLP-1 and GLP-2, and not glucagon, in rat brain and intestine (Mojsov et al., 1986; Drucker and Asa, 1988; Kieffer and Habener, 1999; Mayo et al., 2003), this type of processing is suggested to be null in fish intestine, in which glucagon is produced locally (Plisetskaya and Mommsen, 1996). Moreover, unlike mammals, tissue-specific alternative mRNA splicing of the glucagon gene seems to play an important role in controlling peptide production in different tissues of fish, frog, and chicken (Irwin and Wong, 1995; Yeung and Chow, 2001; Richards and McMurtry, 2008). Clearly, further study on glucagon production in various tissues will be required to elucidate the roles of glucagon in chicken.
In summary, the full-length cDNA sequence encoding chicken glucagon receptor (GCGR-s and GCGR-v1) was cloned in this study. Functional studies confirmed that both GCGR-s and GCGR-v1 can be potently activated by glucagon and are functionally coupled to cAMP-PKA signaling pathway. The RT-PCR assay revealed that glucagon receptor is expressed in all chicken tissues examined, with the greatest expression in the liver. These findings clearly suggest that chicken glucagon plays a wide range of roles in both hepatic and nonhepatic tissues and that its action is likely mediated by GCGR-s and GCGR-v1.
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ACKNOWLEDGMENTS |
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Received for publication June 26, 2008. Accepted for publication August 29, 2008.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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