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Somatostatins and their receptors in fish
Comparative Biochemistry and Physiology Part B 129 Ž2001. 543᎐550
Review
Somatostatins and their receptors in fish Xinwei Lin, Richard E. Peter U Department of Biological Sciences, Uni¨ ersity of Alberta, Edmonton, Alberta T6G 2E9, Canada Received 4 August 2000; received in revised form 18 October 2000; accepted 23 October 2000
Abstract Somatostatin ŽSRIF. is a multigene family of peptides. SRIF-14 is conserved with identical primary structure in species across the vertebrates. The presence of multiple SRIF genes has been demonstrated in a number of fish species. Notably, three distinct SRIF genes have been identified in goldfish. One of these genes, which encodes wPro 2 xSRIF-14, has also been identified in sturgeon and African lungfish, and is closely associated with the amphibian wPro 2 ,Met 13 xSRIF-14 gene and mammalian cortistatin gene. The main neuroendocrine role of SRIF-14 peptide that has been determined in fish is the inhibition of pituitary growth hormone secretion. The functions of SRIF-14 variant or larger forms of SRIF peptide and the regulation of SRIF gene expression remain to be explored. Type one and two SRIF receptors have been identified from goldfish and type three SRIF receptor from an electric fish. Fish SRIF receptors display considerable homology to mammalian counterparts in terms of primary structure and negative coupling to adenylate cyclase. The identification of the multiple gene family of SRIF peptides and multiple types of SRIF receptors in fish opens a new avenue for the study of physiological roles of SRIF, and the molecular and cellular mechanisms of SRIF actions in fish. 䊚 2001 Elsevier Science Inc. All rights reserved. Keywords: Fish; Growth hormone; Somatostatin; Urotensin II; Somatostatin receptor; Gene expression
1. Introduction Somatostatin ŽSRIF. is a tetradecapeptide that was originally isolated from sheep hypothalamus and characterized as a physiological inhibitor of pituitary growth hormone ŽGH . secretion ŽBrazeau et al., 1973.. In mammals, SRIF exists as two biologically active forms, SRIF-14 and its
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Corresponding author. Tel.: q1-780-492-4757; fax: q1780-492-7033. E-mail address: [email protected] ŽR.E. Peter..
NH 2-terminal extension of 14 amino acids, SRIF28 ŽPatel, 1999.. In addition, SRIF is now well established to be a multifunctional peptide widely distributed throughout the nervous system and peripheral tissues ŽPatel, 1999; Tannenbaum and Epelbaum, 1999.. SRIF peptides have been identified and subsequently their cDNAs cloned from anglerfish and channel catfish Žfor review, Lin et al., 1998. approximately 20 years ago. Since then, although the identification of multiple forms of SRIF peptides and recent cloning of multiple SRIF cDNAs have been reported from a wide range of fish
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species Žfor a review, Conlon et al., 1997; Lin et al., 1998., the physiology of SRIF has not been intensively explored in fish. The following review will briefly describe the products of the SRIF multigene family, actions of SRIF peptides, regulation of SRIF gene expression, and very recent identification of SRIF receptors in fish.
2. Somatostatin gene products in fish SRIF-14 has been identified, with the same amino acid sequence, in representatives across the vertebrates. Complementary DNA ŽcDNA. for preprosomatostatin-I ŽPSS-I., which contains SRIF-14 at its C-terminus, has been cloned in several fish species Žfor a review, Lin et al., 1998.. In addition to having PSS-I, teleost fish possess a second SRIF precursor, preprosomatostatin-II ŽPSS-II., which contains wTyr 7, Gly 10 xSRIF-14 or its variant at the C-terminus. The complete cDNA sequence for PSS-II has been identified in anglerfish ŽHobart et al., 1980., rainbow trout ŽMoore et al., 1995, 1999. and goldfish ŽLin et al., 1999a., providing evidence that SRIFs arose from a multigene family. In addition, amino acid sequences of PSS-II gene products ŽSRIF-28 or SRIF-25. obtained directly from isolates of pancreatic islet are known for several teleosts Žfor a review, Conlon et al., 1997; Lin et al., 1998.. Interestingly, several wTyr 7, Gly 10 xSRIF-14 variant sequences were identified from the PSS-II precursor or the long form of peptides derived from PSS-II. For example, SRIF-28 isolated from the pancreas of tilapia contains wTyr 7 , Gly 10 , Leu11 xSRIF-14 at its C terminus ŽNguyen et al., 1995.; SRIF-25 from pancreas and gut of European eel contains wTyr 7, Gly 10 , Pro 11 xSRIF-14 ŽUesaka et al., 1994; Conlon et al., 1988.; goldfish PSS-II precursor deduced from cDNA sequence contains wGlu1, Tyr 7, Gly 10 xSRIF-14 ŽLin et al., 1999a.. Notably, a SRIF-28 peptide was isolated from goldfish intestine ŽUesaka et al., 1995., with five amino acids different from the goldfish SRIF28 deduced from the brain PSS-II cDNA, suggesting that there are at least two forms of SRIF-28 in goldfish. Furthermore, wTyr 7, Gly 10 , Pro 11 x SRIF-14 peptide has also been isolated from the gut of European eel ŽUesaka et al., 1994., indicating that PSS-II could be processed into both 14-amino acid peptide and 25- or 28-amino acid peptide products.
In goldfish brain, three SRIF cDNAs have been recently identified ŽLin et al., 1999a.. Two of them encode for PSS-I and PSS-II, respectively, whereas the third cDNA from goldfish brain encodes for a precursor ŽPSS-III. with wPro 2 xSRIF-14 at its C terminus. wPro 2 xSRIF-14 has been identified previously in Russian sturgeon ŽNishii et al., 1995. and recently cloned from brain of African lungfish ŽTrabucchi et al., 1999.. This is the first time that three distinct SRIF genes have been identified from a single vertebrate species. Phylogenetic analysis demonstrates that the precursor of wPro 2 xSRIF-14 from goldfish is highly homologous to that from African lungfish, and both precursors are grouped with frog wPro 2 ,Met 13 xSRIF-14 precursor and mammalian cortistatin ŽCST. precursors. Generally, PSS-I gene product is widely distributed in brain and peripheral tissues including the gastrointestinal ŽGI. tract. However, mammalian CST gene expression is restricted to the brain with functions in neuronal depression and sleep modulation Žde Lecea et al., 1996; Fukusumi et al., 1997.. In frog, wPro 2 ,Met 13 x gene is also expressed restricted to the brain ŽTostivint et al., 1996.. Similarly, wPro 2 xSRIF-14 gene is only expressed in brain of African lungfish ŽTrabucchi et al., 1999.. In goldfish, PSS-I and PSS-II genes are expressed in brain and peripheral tissues, such as the GI tract; whereas, PSS-III ŽwPro 2 xSRIF-14. gene is expressed only in the brain ŽLin et al., 1999a.. The restricted brain expression of the third SRIF gene supports a close phylogenetic relationship between the members in this gene group. Urotensin II Ž11- to 14-amino acid peptide. was originally isolated from the urophysis, the hormone-secretory organ of the caudal neurosecretory system of teleost fish Žfor review, Bern et al., 1985.. Urotensin II has also been identified from amphibian Žfrog. and mammalian species Žhuman, mouse, rat and pig. Žfor review, Davenport and Maguire, 2000.. All urotensin II identified so far share a common cyclic sequence Ž ᎐Cys᎐Phe᎐Trp᎐Lys᎐Tyr᎐Cys᎐ ., which is structurally similar to that in the functionally important central region of SRIF-14 Ž ᎐ Phe ᎐ Trp᎐Lys᎐Thr᎐ .. However, cloning and sequence analysis of the cDNA encoding fish, frog or mammalian urotensin II has shown that precursor sequence identity with PSS-I outside this cyclic region is poor, suggesting that the urotensin II and SRIF genes were not derived from a common
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ancestor Žfor review, Conlon et al., 1997; Coulouarn et al., 1998.. Recently, urotensin II was identified as the endogenous ligand of a G protein-coupled orphan receptor ŽGRP14. ŽMori et al., 1999; Liu et al., 1999; Ames et al., 1999.. The GRP14 is most similar to members of the SRIF receptor family ŽMarchese et al., 1995; Liu et al., 1999.. However, pharmacological studies of GPR14 showed that SRIF-14 and human cortistatin-17 did not activate GPR14 at high Ž1 M. concentration ŽLiu et al., 1999.. In addition, frog urotensin II did not displace w 125 I-Tyr 0 , DTrp 8 xSRIF-14 binding on frog brain slices ŽTostivint et al., 1996.. These findings further support the evidence that SRIF and urotensin II do not belong to the same gene family.
3. Actions of somatostatins in fish In fish, most of the physiological studies of SRIF have focused on the regulation of pancreatic hormones associated with development and metabolism, and on the regulation of pituitary GH secretion. In rainbow trout, both gene I and gene II products ŽSRIF-14 and SRIF-25. have physiological roles, especially with regard to depressing plasma insulin and glucagon levels, and stimulating glycogenolysis and lipolysis ŽSheridan, 1994; Sheridan and Kao, 1998.. In addition, the lipolysis induced by SRIF peptides is involved in salmonid smoltification-associated changes in the lipid metabolism ŽSheridan and Kao, 1998.. In lamprey, SRIF-14 generally stimulates lipid depletion and inhibits lipid deposition in storage sites, resulting in elevated plasma fatty acid levels ŽKao et al., 1998.. The inhibitory effect of SRIF-14 on pituitary GH release in vitro or in vivo has been widely demonstrated in a number of teleost species Žfor a review, Lin et al., 1998.. As in mammals, SRIF14 is a potent inhibitor of the basal and stimulated GH release in vivo and in vitro in teleost fishes. However, SRIF-14 does not suppress expression of GH gene in rainbow trout ŽYada and Hirano, 1992. or tilapia ŽMelamed et al., 1996.. Identification of multiple forms of SRIF peptides in teleost fish raises a question about the effects of native SRIF-14 variant or its N terminal extended form on pituitary GH secretion. In goldfish, previous studies showed that mammalian
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SRIF-28 is equipotent with SRIF-14 in reducing basal GH secretion; however, catfish SRIF-22 and salmon SRIF-25 were not active in suppressing GH release in the goldfish ŽMarchant et al., 1987.. In coho salmon, SRIF-14 and mammalian SRIF25 and SRIF-28 significantly decreased plasma GH concentrations ŽDiez et al., 1992.. In European eel, SRIF-14, mammalian SRIF-28 or rat cortistatin inhibited GH release from pituitary cells ŽRousseau et al., 1998.. wPro 2 xSRIF-14 inhibited GH release from rainbow trout pituitary, with similar potency to SRIF-14. Similarly, wPro 2 xSRIF-14 and SRIF-14, two of the native SRIF forms in goldfish, inhibit basal and stimulated GH release from goldfish pituitary fragments in vitro, with similar potencies ŽLin et al., 1999a.. Although catfish SRIF-22 has not been tested in catfish, it inhibits GH secretion from rat anterior pituitary cells ŽOyama et al., 1980.. It has been reported that SRIF-14 is effective in blocking prolactin ŽPRL. release in vitro from the pituitary of tilapia ŽGrau et al., 1987.. In addition, SRIF-14 has also been shown to be involved in the regulation of salt and water fluxes across the seawater eel intestine ŽUesaka et al., 1994.. In mammals, SRIF has also shown to inhibit secretion of other pituitary hormones such as thyrotrophin and corticotrophin ŽTannenbaum and Epelbaum, 1999.; however, similar actions of SRIF in fish have not been examined to date.
4. Regulation of somatostatin gene expression in fish In our recent studies, dopaminergic regulation of three SRIF mRNAs in goldfish brain has been examined ŽOtto et al., 1999.. The results provide evidence for inhibitory andror stimulatory regulation of the three SRIF genes by dopamine through both D1-like and D2-like receptors ŽOtto et al., 1999.. There are also differences in the effects of dopamine D2 agonist treatment on expression of the three SRIF genes in goldfish brain in early stages of gonadal recrudescence compared to fish in late stages of gonadal recrudescence, and between male and female fish, suggesting that sex steroids have influences on the actions of dopamine on SRIF gene expression. Indeed, seasonal variations in the levels of the three SRIF mRNAs were observed in goldfish, with differential patterns between the three
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mRNAs and differences between the sexes ŽLin et al., 1999a.. Our preliminary results also demonstrate that estradiol affects PSS-I ŽSRIF-14. mRNA levels in the telecephalon-preoptic region and hypothalamus of sexually regressed goldfish ŽOtto and Peter, unpublished results .. In rainbow trout, it was recently reported that nutrients such as glucose stimulates PSS-I and PSS-II gene expression in the Brockmann body in vivo and in vitro ŽMelroe et al., 2000; Ehrman et al., 2000.. The glucose-stimulated expression of PSS-I and PSS-II mRNAs requires the uptake and subsequent metabolism of the sugar in pancreatic islets.
5. Somatostatin receptors in fish SRIF exerts diverse inhibitory actions through binding to specific plasma membrane receptors. Since 1991, five types of SRIF receptor have been identified by molecular cloning of their cDNAs or genes in several mammalian species and named SSTR1 to SSTR5 Žfor review, Hoyer et al., 1995; Patel, 1999; Tannenbaum and Epelbaum, 1999.. Since the relationship between recombinant receptors and endogenously expressed receptors is not yet fully established, in 1995 an IUPHAR subcommittee recommended to refer to them as recombinant entities, using the conventional lower case nomenclature, i.e. sst 1 to sst 5 , until sufficient evidence for in vivo function is available ŽHoyer et al., 1995.. All five types of mammalian sst are members of the rhodopsin family of guanine nucleotide binding ŽG. protein-coupled receptor ŽGPCR.. Overall, there is 39᎐57% sequence identity among the various members of the sst family. All the mammalian sst receptors cloned so far contain a highly conserved sequence motif, YANSCANPIrVLY, in the seventh transmembrane domain ŽTMD., which serves as a signature sequence for this receptor family. Genes for sst 1 , sst 3 , sst 4 , and sst 5 are intronless, whereas sst 2 gene displays a cryptic intron at the 3⬘ end of the coding segment, which gives rise to two spliced variants, a long Žsst 2A . form and a C-terminal tail-truncated short Žsst 2B . form ŽVanetti et al., 1992; Patel et al., 1993; Schindler et al., 1998.. All five subtypes of sst bind SRIF-14 and mammalian SRIF-28 with high affinity Žnanomolar., whereas sst 5 exhibits some selectivity for SRIF-28. However, based on their structural and pharmacologi-
cal characteristics the five receptor types can be classified into two main classes of receptors: sst 2rsst 3rsst 5 subgroup and sst 1rsst 4 subgroup, which are pharmacologically and functionally equivalent to the previously defined SRIF-1 and SRIF-2 classes of receptors, respectively ŽDournaud et al., 2000.. SRIF-1 receptors bind octapeptide Žoctreotide or SMS201-995. and hexapeptide Žseglitide or MK678. SRIF analogs, whereas SRIF-2 receptors are insensitive to these compounds. In mammals, studies of receptor mRNA distribution and receptor protein localization have revealed a complicated expression pattern of sst receptors throughout the central nervous system and in a wide range of peripheral tissues, with an overlapping but differential pattern that is subtype-selective, tissue-specific, and species-specific ŽPatel, 1999.. All five types of sst receptors are expressed throughout brain; sst 1 is the predominant hypothalamic subtype ŽPatel, 1999.. In pituitary, all five types of sst receptors are expressed in the major cell types. Sst 5 and sst 2 are the principle subtypes expressed in the rat pituitary somatotrophes ŽKumar et al., 1997.. The physiological roles of each receptor subtype have been assessed with mammalian pituitary cells or transfected cells expressing each receptor subtype using subtype selective agonists, with selective antisense oligodeoxynucleotides to block the expression of each receptor gene, or with genetic animal models with selective deletion Žgene knock-out mice. of sst1 or sst2 receptor gene. Overall, these studies showed that sst 1 , sst 2 and sst 5 are involved in the inhibition of GH release ŽZheng et al., 1997; Rohrer et al., 1998; Parmar et al., 1999; Kreienkamp et al., 1999; Lanneau et al., 2000; Park et al., 2000. where sst 2 and sst 5 mediate inhibition of glucagon secretion and insulin secretion, respectively Žfor review, Benali et al., 2000.. In teleosts, the SRIF binding sites in brain have been characterized in goldfish ŽCardenas et al., 2000.. The characteristics of the SRIF binding sites have also been reported in liver membrane preparations and hepatocytes of rainbow trout ŽPesek et al., 1998; Pesek and Sheridan, 1996.. The distribution of the SRIF binding sites in brain has been reported in African lungfish ŽVallarino et al., 1997., an electric fish Apteronotus leptorhynchus, ŽZupanc et al., 1994. and goldfish ŽCardenas et al., 2000.. Overall, these studies show that SRIF-14 binding sites are widely dis-
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tributed throughout brain, with high density in the forebrain, optic tectum, and some regions of the hindbrain, suggesting multiple functions of SRIF-14 as a neurotransmitter andror a neuromodulator in fish. SRIF-14 binding sites have also been found on granulosa and theca cells of the ovary of an African lungfish ŽMasini et al., 1999., implicating SRIF in the control of ovarian function. Two type one SRIF receptor cDNAs were cloned from goldfish brain ŽLin et al., 1999b.. Both receptor mRNAs are widely distributed throughout goldfish brain, whereas only one receptor mRNA was detected in the pituitary. The two cDNAs share 92% similarity in nucleotide sequence and 98% similarity in the deduced amino acid sequences, and are presumably derived from duplicate genes, as goldfish are tetraploid. Two cDNAs encode two 367-amino acid goldfish type one SRIF receptors Žsst 1A and sst 1B ., which have 75᎐76% similarity to mammalian sst 1 , and 39᎐55% similarities to other mammalian sst subtypes Žsst 2 ᎐ 5 .. Both SRIF-14 and wPro 2 xSRIF14 significantly inhibited forskolin-stimulated cAMP release in COS-7 cells transiently expressing the cloned goldfish sst 1A or sst 1B receptors ŽLin et al., 1999b., suggesting coupling of the receptors to inhibition of adenylate cyclase. In addition, there were no apparent differences between two goldfish sst 1 receptors in their potencies for SRIF-14 and wPro 2 xSRIF-14, suggesting that two receptors display similar affinities for both peptides ŽLin et al., 1999b.. A type three sst receptor has been identified from Apteronotus albifrons ŽZupanc et al., 1999.. The Apteronotus sst 3 Žasst 3 . exhibits 56᎐59% sequence similarity with mammalian sst 3 . Expression of the sst 3 mRNA in brain was detected by RT-PCR. The pharmacological studies revealed that the fish sst 3 has a pharmacological profile compatible with that of mammalian SRIF-1 receptor group ŽSiehler et al., 1999.. Both SRIF-14 and mammalian SRIF-28 potently inhibited forskolin-stimulated adenylate cyclase activity in CCL39 cells expressing asst 3 receptors; this effect was blocked by pertussis toxin, suggesting coupling of the sst 3 receptor to Gi ␣ andror Go ␣ G-proteins ŽSiehler et al., 1999.. Radioligand binding studies were performed with four radioligands selective for mammalian SRIF receptors in CCL39 cells expressing the asst 3 receptors ŽSiehler et al., 1999.. w 125 I-Leu 8 , D-Trp 22 ,
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Tyr 25 xSRIF-28 Žmammalian SRIF-28 analog. and w 125 I-Tyr 10 xCST-14, and SRIF-14 analogs w 125 IxCGP 23996 and w 125 IxTyr 3-octreotide bind the cloned asst 3 receptors with high affinity. SRIF-14, mammalian SRIF-28, mammalian SRIF25 or rat cortistatin-14 displaced the radioligand binding on sst 3 with similar high affinity. However, catfish SRIF-22 exhibited low affinity for the sst 3 receptors. We have recently cloned a type two SRIF receptor from goldfish brain ŽLin et al., 2000.. The amino acid sequence of goldfish sst 2 has 61 and 62% similarity to human and rat sst 2 , respectively, and 41᎐47% similarities to other mammalian sst subtypes, and 42% similarity to both goldfish sst 1 receptors. The distribution and expression levels of the sst 2 receptor mRNA in brain regions and pituitary are different from the sst 1 receptor mRNAs. The sst 2 mRNA levels in pituitary are significantly higher than in brain regions, consistent with the findings in mammals that sst 2 and sst 5 are predominantly expressed in pituitary somatotrophs and involved in the direct regulation of GH secretion. The cloned sst 2 receptors are able to bind SRIF-14 and wPro 2 xSRIF14 and couple to inhibition of adenylate cyclase.
6. Concluding remarks SRIF-14 is conserved with identical primary structure in all classes of vertebrate. There is evidence for the expression of second andror third SRIF genes in a single vertebrate species, especially in the lower vertebrates. Three distinct SRIF genes have been identified in goldfish brain, making this species an ideal model for study of the SRIF gene family. Although our studies demonstrate that all three SRIF forms inhibit pituitary GH release in vitro ŽLin et al., 1999a, Chang and Peter, unpublished results, 2000., which SRIF is the primary neuroendocrine regulator of GH release in goldfish is not yet clear. Identification of multiple types of SRIF receptors raises a question whether a given physiological response is selective for one type of receptors or whether multiple types of receptors are involved. In addition, whether there is any particular link between a form of SRIF peptide and a receptor type is unknown. Overlapping expression of goldfish sst 1 and sst 2 receptors in pituitary and some brain regions implicates the involvement of multiple
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types of receptors in a physiological role of SRIF. Similarly, it has been proposed that sst may operate in concert, rather than as individual members in mammals, as individual target cells typically express multiple sst types ŽPatel, 1999.. Furthermore, a recent study demonstrated that human sst 5 can form agonist-dependent functional heterodimers with sst 1 but not with sst 4 , suggesting a direct molecular interaction between different sst subtypes ŽRocheville et al., 2000..
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M.A., 2000. Glucose regulates pancreatic preprosomatostatin I expression. FEBS Lett. 465, 115᎐118. Moore, C.A., Kittilson, J.D., Kahl, S.K., Sheridan, M.A., 1995. Isolation and characterization of a cDNA encoding for preprosomatostatin containing wTyr 7, Gly 10 x-somatostatin-14 from the endocrine pancreas of rainbow trout, Oncorhynchus mykiss. Gen. Comp. Endocrinol. 98, 253᎐261. Moore, C.A., Kittilson, J.D., Ehrman, M.M., Sheridan, M.A., 1999. Rainbow trout Ž Oncorhynchus mykiss. possess two somatostatin mRNAs that are differentially expressed. Am. J. Physiol. 277, R1553᎐R1561. Mori, M., Sugo, T., Abe, M. et al., 1999. Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR ŽGPR14.. Biochem. Biophys. Res. Commun. 265, 123᎐129. Nguyen, T.M., Wright Jr., J.R., Neilsen, P.F., Conlon, J.M., 1995. Characterization of the pancreatic hormones from the Brockmann body of the tilapia: implications for islet xenograft studies. Comp. Biochem. Physiol. 111C, 33᎐44. Nishii, M., Moverus, B., Bukovskaya, O.S., Yakahashi, A., Kawauchi, H., 1995. Isolation and characterization of wPro 2 xsomatostatin-14 and melanotropins from Russian sturgeon, Acipenser gueldenstaedti Brandt. Gen. Comp. Endocrinol. 99, 6᎐12. Otto, C.J., Lin, X., Peter, R.E., 1999. Dopaminergic regulation of three somatostatin mRNAs in goldfish brain. Regul. Peptides 83, 97᎐104. Oyama, H., Bradshaw, R.A., Bates, O.J., Permutt, A., 1980. Amino acid sequence of catfish pancreatic somatostatin I. J. Biol. Chem. 155, 2251᎐2254. Park, S., Kamegai, J., Johnson, T.A., Frohman, L.A., Kineman, R.D., 2000. Modulation of pituitary somatostatin receptor subtype Žsst1᎐5. messenger ribonucleic acid levels by changes in the growth hormone axis. Endocrinology 141, 3556᎐3563. Parmar, R.M., Chan, W.W.-S., Dashkevicz, M. et al., 1999. Nonpeptidyl somatostatin agonists demonstrate that sst2 and sst5 inhibit stimulated growth hormone secretion from rat anterior pituitary cells. Biochem. Biophys. Res. Commun. 263, 276᎐280. Patel, Y.C., 1999. Somatostatin and its receptor family. Front. Neuroendocrinol. 20, 157᎐198. Patel, Y.C., Greenwood, M., Kent, G., Panetta, R., Srikant, C.B., 1993. Multiple gene transcripts of the somatostatin receptor SSTR2: tissue selective distribution and cAMP regulation. Biochem. Biophys. Res. Commun. 192, 288᎐294. Pesek, M.J., Sheridan, M.A., 1996. Fasting alters somatostatin binding to liver membranes of rainbow trout Ž Oncorhynchus mykiss.. J. Endocrinol. 150, 179᎐186. Pesek, M.J., Howe, N., Sheridan, M.A., 1998. Somatostatin binding to hepatocytes isolated from rain-
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bow trout, Oncorhynchus mykiss, is modulated by insulin and glucagon. Gen. Comp. Endocrinol. 112, 183᎐190. Rocheville, M., Lange, D.C., Kumar, U., Sasi, R., Patel, R.C., Patel, Y.C., 2000. Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. J. Biol. Chem. 275, 7862᎐7869. Rohrer, L., Birzin, E.T., Mosley, R.T. et al., 1998. Rapid identification of subtype-selective agonists of the somatostatin receptor through combinational chemistry. Science 282, 737᎐740. Rousseau, K., Huang, Y.-S., Le Belle, N. et al., 1998. Long-term inhibitory effects of somatostatin and insulin-like growth factor 1 on growth hormone release by serum-free primary culture of pituitary cells from European eel Ž Anguilla anguilla.. Neuroendocrinology 67, 301᎐309. Schindler, M., Kidd, E.J., Carruthers, A.M. et al., 1998. Molecular cloning and functional characterization of a rat somatostatin sst 2Žb. receptor splice variant. Br. J. Pharmacol. 125, 209᎐217. Sheridan, M.A., 1994. Regulation of lipid metabolism in poikilothermic vertebrates. Comp. Biochem. Physiol. 107B, 495᎐508. Sheridan, M.A., Kao, Y.-H., 1998. Regulation of metamorphosis-associated changes in the lipid metabolism of selected vertebrates. Am. Zool. 38, 350᎐368. Siehler, S., Zupanc, G.K.H., Seuwen, K., Hoyer, D., 1999. Characterization of the fish sst 3 receptor, a member of the SRIF1 receptor family: atypical pharmacological features. Neuropharmacology 38, 449᎐462. Tannenbaum, G.S., Epelbaum, J., 1999. Somatostatin. In: Kostyo, J.L., Goodman, H.M. ŽEds.., . Handbook of Physiology, Section 7: The Endocrine System, V. Hormonal Control of Growth. Oxford University Press, New York, NY, pp. 221᎐265. Tostivint, H., Lihrmann, I., Bucharles, C. et al., 1996. Occurrence of two somatostatin variants in the frog brain: characterization of the cDNAs, distribution of the mRNAs and receptor-binding of the peptides. Proc. Natl. Acad. Sci. USA 93, 12605᎐12610. Trabucchi, M., Tostivint, H., Lihrmann, I., Jegou, S., ´
Vallarino, M., Vaudry, H., 1999. Molecular cloning of the cDNAs and distribution of the mRNAs encoding two somatostatin precursors in the African lungfish Protopterus annectens. J. Comp. Neurol. 410, 643᎐652. Uesaka, T., Yano, K., Yamasaki, M., Nagashima, K., Ando, M., 1994. Somatostatin-related peptides isolated from the eel gut: effects on ion and water absorption across the intestine of the seawater eel. J. Exp. Biol. 188, 205᎐216. Uesaka, T., Yano, K., Yamasaki, M., Ando, M., 1995. Somatostatin-, vasoactive intestinal peptide-, and granulin-like peptides isolated from intestinal extracts of goldfish, Carassius auratus. Gen. Comp. Endocrinol. 99, 187᎐306. Vallarino, M., Trabucchi, M., Masini, M.A., Chartrel, N., Vaudry, H., 1997. Immunocytochemical localization of somatostatin and autoradiographic distribution of somatostatin binding sites in the brain of the African lungfish, Protopterus annectens. J. Comp. Neurol. 388, 337᎐353. Vanetti, M., Kouba, M., Wang, X., Vogt, G., Hollt, ¨ V., 1992. Cloning and expression of a novel mouse somatostatin receptor ŽSSTR2B.. FEBS Lett. 311, 290᎐294. Yada, T., Hirano, T., 1992. Inhibition of growth hormone synthesis by somatostatin in cultured pituitary of rainbow trout. J. Comp. Physiol. 162, 575᎐580. Zheng, H., Bailey, A., Jiang, M.H. et al., 1997. Somatostatin receptor subtype 2 knockout mice are refractory to growth hormone-negative feedback on arcuate neurons. Mol. Endocrinol. 11, 1709᎐1717. Zupanc, G.K.H., Cecyre, D., Maler, L., Zupanc, M.M., ´ Quirion, R., 1994. The distribution of somatostatin binding sites in the brain of gynmotiform fish, Apteronotus leptorhynchus. J. Chem. Neuroanat. 7, 49᎐63. Zupanc, G.K.H., Siehler, S., Jones, E.M.C. et al., 1999. Molecular cloning and pharmacological characterization of a somatostatin receptor subtype in the gymnotiform fish Apteronotus albifrons. Gen. Comp. Endocrinol. 115, 333᎐345.
Review
Somatostatins and their receptors in fish Xinwei Lin, Richard E. Peter U Department of Biological Sciences, Uni¨ ersity of Alberta, Edmonton, Alberta T6G 2E9, Canada Received 4 August 2000; received in revised form 18 October 2000; accepted 23 October 2000
Abstract Somatostatin ŽSRIF. is a multigene family of peptides. SRIF-14 is conserved with identical primary structure in species across the vertebrates. The presence of multiple SRIF genes has been demonstrated in a number of fish species. Notably, three distinct SRIF genes have been identified in goldfish. One of these genes, which encodes wPro 2 xSRIF-14, has also been identified in sturgeon and African lungfish, and is closely associated with the amphibian wPro 2 ,Met 13 xSRIF-14 gene and mammalian cortistatin gene. The main neuroendocrine role of SRIF-14 peptide that has been determined in fish is the inhibition of pituitary growth hormone secretion. The functions of SRIF-14 variant or larger forms of SRIF peptide and the regulation of SRIF gene expression remain to be explored. Type one and two SRIF receptors have been identified from goldfish and type three SRIF receptor from an electric fish. Fish SRIF receptors display considerable homology to mammalian counterparts in terms of primary structure and negative coupling to adenylate cyclase. The identification of the multiple gene family of SRIF peptides and multiple types of SRIF receptors in fish opens a new avenue for the study of physiological roles of SRIF, and the molecular and cellular mechanisms of SRIF actions in fish. 䊚 2001 Elsevier Science Inc. All rights reserved. Keywords: Fish; Growth hormone; Somatostatin; Urotensin II; Somatostatin receptor; Gene expression
1. Introduction Somatostatin ŽSRIF. is a tetradecapeptide that was originally isolated from sheep hypothalamus and characterized as a physiological inhibitor of pituitary growth hormone ŽGH . secretion ŽBrazeau et al., 1973.. In mammals, SRIF exists as two biologically active forms, SRIF-14 and its
U
Corresponding author. Tel.: q1-780-492-4757; fax: q1780-492-7033. E-mail address: [email protected] ŽR.E. Peter..
NH 2-terminal extension of 14 amino acids, SRIF28 ŽPatel, 1999.. In addition, SRIF is now well established to be a multifunctional peptide widely distributed throughout the nervous system and peripheral tissues ŽPatel, 1999; Tannenbaum and Epelbaum, 1999.. SRIF peptides have been identified and subsequently their cDNAs cloned from anglerfish and channel catfish Žfor review, Lin et al., 1998. approximately 20 years ago. Since then, although the identification of multiple forms of SRIF peptides and recent cloning of multiple SRIF cDNAs have been reported from a wide range of fish
1096-4959r01r$ - see front matter 䊚 2001 Elsevier Science Inc. All rights reserved. PII: S 1 0 9 6 - 4 9 5 9 Ž 0 1 . 0 0 3 6 2 - 1
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species Žfor a review, Conlon et al., 1997; Lin et al., 1998., the physiology of SRIF has not been intensively explored in fish. The following review will briefly describe the products of the SRIF multigene family, actions of SRIF peptides, regulation of SRIF gene expression, and very recent identification of SRIF receptors in fish.
2. Somatostatin gene products in fish SRIF-14 has been identified, with the same amino acid sequence, in representatives across the vertebrates. Complementary DNA ŽcDNA. for preprosomatostatin-I ŽPSS-I., which contains SRIF-14 at its C-terminus, has been cloned in several fish species Žfor a review, Lin et al., 1998.. In addition to having PSS-I, teleost fish possess a second SRIF precursor, preprosomatostatin-II ŽPSS-II., which contains wTyr 7, Gly 10 xSRIF-14 or its variant at the C-terminus. The complete cDNA sequence for PSS-II has been identified in anglerfish ŽHobart et al., 1980., rainbow trout ŽMoore et al., 1995, 1999. and goldfish ŽLin et al., 1999a., providing evidence that SRIFs arose from a multigene family. In addition, amino acid sequences of PSS-II gene products ŽSRIF-28 or SRIF-25. obtained directly from isolates of pancreatic islet are known for several teleosts Žfor a review, Conlon et al., 1997; Lin et al., 1998.. Interestingly, several wTyr 7, Gly 10 xSRIF-14 variant sequences were identified from the PSS-II precursor or the long form of peptides derived from PSS-II. For example, SRIF-28 isolated from the pancreas of tilapia contains wTyr 7 , Gly 10 , Leu11 xSRIF-14 at its C terminus ŽNguyen et al., 1995.; SRIF-25 from pancreas and gut of European eel contains wTyr 7, Gly 10 , Pro 11 xSRIF-14 ŽUesaka et al., 1994; Conlon et al., 1988.; goldfish PSS-II precursor deduced from cDNA sequence contains wGlu1, Tyr 7, Gly 10 xSRIF-14 ŽLin et al., 1999a.. Notably, a SRIF-28 peptide was isolated from goldfish intestine ŽUesaka et al., 1995., with five amino acids different from the goldfish SRIF28 deduced from the brain PSS-II cDNA, suggesting that there are at least two forms of SRIF-28 in goldfish. Furthermore, wTyr 7, Gly 10 , Pro 11 x SRIF-14 peptide has also been isolated from the gut of European eel ŽUesaka et al., 1994., indicating that PSS-II could be processed into both 14-amino acid peptide and 25- or 28-amino acid peptide products.
In goldfish brain, three SRIF cDNAs have been recently identified ŽLin et al., 1999a.. Two of them encode for PSS-I and PSS-II, respectively, whereas the third cDNA from goldfish brain encodes for a precursor ŽPSS-III. with wPro 2 xSRIF-14 at its C terminus. wPro 2 xSRIF-14 has been identified previously in Russian sturgeon ŽNishii et al., 1995. and recently cloned from brain of African lungfish ŽTrabucchi et al., 1999.. This is the first time that three distinct SRIF genes have been identified from a single vertebrate species. Phylogenetic analysis demonstrates that the precursor of wPro 2 xSRIF-14 from goldfish is highly homologous to that from African lungfish, and both precursors are grouped with frog wPro 2 ,Met 13 xSRIF-14 precursor and mammalian cortistatin ŽCST. precursors. Generally, PSS-I gene product is widely distributed in brain and peripheral tissues including the gastrointestinal ŽGI. tract. However, mammalian CST gene expression is restricted to the brain with functions in neuronal depression and sleep modulation Žde Lecea et al., 1996; Fukusumi et al., 1997.. In frog, wPro 2 ,Met 13 x gene is also expressed restricted to the brain ŽTostivint et al., 1996.. Similarly, wPro 2 xSRIF-14 gene is only expressed in brain of African lungfish ŽTrabucchi et al., 1999.. In goldfish, PSS-I and PSS-II genes are expressed in brain and peripheral tissues, such as the GI tract; whereas, PSS-III ŽwPro 2 xSRIF-14. gene is expressed only in the brain ŽLin et al., 1999a.. The restricted brain expression of the third SRIF gene supports a close phylogenetic relationship between the members in this gene group. Urotensin II Ž11- to 14-amino acid peptide. was originally isolated from the urophysis, the hormone-secretory organ of the caudal neurosecretory system of teleost fish Žfor review, Bern et al., 1985.. Urotensin II has also been identified from amphibian Žfrog. and mammalian species Žhuman, mouse, rat and pig. Žfor review, Davenport and Maguire, 2000.. All urotensin II identified so far share a common cyclic sequence Ž ᎐Cys᎐Phe᎐Trp᎐Lys᎐Tyr᎐Cys᎐ ., which is structurally similar to that in the functionally important central region of SRIF-14 Ž ᎐ Phe ᎐ Trp᎐Lys᎐Thr᎐ .. However, cloning and sequence analysis of the cDNA encoding fish, frog or mammalian urotensin II has shown that precursor sequence identity with PSS-I outside this cyclic region is poor, suggesting that the urotensin II and SRIF genes were not derived from a common
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ancestor Žfor review, Conlon et al., 1997; Coulouarn et al., 1998.. Recently, urotensin II was identified as the endogenous ligand of a G protein-coupled orphan receptor ŽGRP14. ŽMori et al., 1999; Liu et al., 1999; Ames et al., 1999.. The GRP14 is most similar to members of the SRIF receptor family ŽMarchese et al., 1995; Liu et al., 1999.. However, pharmacological studies of GPR14 showed that SRIF-14 and human cortistatin-17 did not activate GPR14 at high Ž1 M. concentration ŽLiu et al., 1999.. In addition, frog urotensin II did not displace w 125 I-Tyr 0 , DTrp 8 xSRIF-14 binding on frog brain slices ŽTostivint et al., 1996.. These findings further support the evidence that SRIF and urotensin II do not belong to the same gene family.
3. Actions of somatostatins in fish In fish, most of the physiological studies of SRIF have focused on the regulation of pancreatic hormones associated with development and metabolism, and on the regulation of pituitary GH secretion. In rainbow trout, both gene I and gene II products ŽSRIF-14 and SRIF-25. have physiological roles, especially with regard to depressing plasma insulin and glucagon levels, and stimulating glycogenolysis and lipolysis ŽSheridan, 1994; Sheridan and Kao, 1998.. In addition, the lipolysis induced by SRIF peptides is involved in salmonid smoltification-associated changes in the lipid metabolism ŽSheridan and Kao, 1998.. In lamprey, SRIF-14 generally stimulates lipid depletion and inhibits lipid deposition in storage sites, resulting in elevated plasma fatty acid levels ŽKao et al., 1998.. The inhibitory effect of SRIF-14 on pituitary GH release in vitro or in vivo has been widely demonstrated in a number of teleost species Žfor a review, Lin et al., 1998.. As in mammals, SRIF14 is a potent inhibitor of the basal and stimulated GH release in vivo and in vitro in teleost fishes. However, SRIF-14 does not suppress expression of GH gene in rainbow trout ŽYada and Hirano, 1992. or tilapia ŽMelamed et al., 1996.. Identification of multiple forms of SRIF peptides in teleost fish raises a question about the effects of native SRIF-14 variant or its N terminal extended form on pituitary GH secretion. In goldfish, previous studies showed that mammalian
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SRIF-28 is equipotent with SRIF-14 in reducing basal GH secretion; however, catfish SRIF-22 and salmon SRIF-25 were not active in suppressing GH release in the goldfish ŽMarchant et al., 1987.. In coho salmon, SRIF-14 and mammalian SRIF25 and SRIF-28 significantly decreased plasma GH concentrations ŽDiez et al., 1992.. In European eel, SRIF-14, mammalian SRIF-28 or rat cortistatin inhibited GH release from pituitary cells ŽRousseau et al., 1998.. wPro 2 xSRIF-14 inhibited GH release from rainbow trout pituitary, with similar potency to SRIF-14. Similarly, wPro 2 xSRIF-14 and SRIF-14, two of the native SRIF forms in goldfish, inhibit basal and stimulated GH release from goldfish pituitary fragments in vitro, with similar potencies ŽLin et al., 1999a.. Although catfish SRIF-22 has not been tested in catfish, it inhibits GH secretion from rat anterior pituitary cells ŽOyama et al., 1980.. It has been reported that SRIF-14 is effective in blocking prolactin ŽPRL. release in vitro from the pituitary of tilapia ŽGrau et al., 1987.. In addition, SRIF-14 has also been shown to be involved in the regulation of salt and water fluxes across the seawater eel intestine ŽUesaka et al., 1994.. In mammals, SRIF has also shown to inhibit secretion of other pituitary hormones such as thyrotrophin and corticotrophin ŽTannenbaum and Epelbaum, 1999.; however, similar actions of SRIF in fish have not been examined to date.
4. Regulation of somatostatin gene expression in fish In our recent studies, dopaminergic regulation of three SRIF mRNAs in goldfish brain has been examined ŽOtto et al., 1999.. The results provide evidence for inhibitory andror stimulatory regulation of the three SRIF genes by dopamine through both D1-like and D2-like receptors ŽOtto et al., 1999.. There are also differences in the effects of dopamine D2 agonist treatment on expression of the three SRIF genes in goldfish brain in early stages of gonadal recrudescence compared to fish in late stages of gonadal recrudescence, and between male and female fish, suggesting that sex steroids have influences on the actions of dopamine on SRIF gene expression. Indeed, seasonal variations in the levels of the three SRIF mRNAs were observed in goldfish, with differential patterns between the three
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mRNAs and differences between the sexes ŽLin et al., 1999a.. Our preliminary results also demonstrate that estradiol affects PSS-I ŽSRIF-14. mRNA levels in the telecephalon-preoptic region and hypothalamus of sexually regressed goldfish ŽOtto and Peter, unpublished results .. In rainbow trout, it was recently reported that nutrients such as glucose stimulates PSS-I and PSS-II gene expression in the Brockmann body in vivo and in vitro ŽMelroe et al., 2000; Ehrman et al., 2000.. The glucose-stimulated expression of PSS-I and PSS-II mRNAs requires the uptake and subsequent metabolism of the sugar in pancreatic islets.
5. Somatostatin receptors in fish SRIF exerts diverse inhibitory actions through binding to specific plasma membrane receptors. Since 1991, five types of SRIF receptor have been identified by molecular cloning of their cDNAs or genes in several mammalian species and named SSTR1 to SSTR5 Žfor review, Hoyer et al., 1995; Patel, 1999; Tannenbaum and Epelbaum, 1999.. Since the relationship between recombinant receptors and endogenously expressed receptors is not yet fully established, in 1995 an IUPHAR subcommittee recommended to refer to them as recombinant entities, using the conventional lower case nomenclature, i.e. sst 1 to sst 5 , until sufficient evidence for in vivo function is available ŽHoyer et al., 1995.. All five types of mammalian sst are members of the rhodopsin family of guanine nucleotide binding ŽG. protein-coupled receptor ŽGPCR.. Overall, there is 39᎐57% sequence identity among the various members of the sst family. All the mammalian sst receptors cloned so far contain a highly conserved sequence motif, YANSCANPIrVLY, in the seventh transmembrane domain ŽTMD., which serves as a signature sequence for this receptor family. Genes for sst 1 , sst 3 , sst 4 , and sst 5 are intronless, whereas sst 2 gene displays a cryptic intron at the 3⬘ end of the coding segment, which gives rise to two spliced variants, a long Žsst 2A . form and a C-terminal tail-truncated short Žsst 2B . form ŽVanetti et al., 1992; Patel et al., 1993; Schindler et al., 1998.. All five subtypes of sst bind SRIF-14 and mammalian SRIF-28 with high affinity Žnanomolar., whereas sst 5 exhibits some selectivity for SRIF-28. However, based on their structural and pharmacologi-
cal characteristics the five receptor types can be classified into two main classes of receptors: sst 2rsst 3rsst 5 subgroup and sst 1rsst 4 subgroup, which are pharmacologically and functionally equivalent to the previously defined SRIF-1 and SRIF-2 classes of receptors, respectively ŽDournaud et al., 2000.. SRIF-1 receptors bind octapeptide Žoctreotide or SMS201-995. and hexapeptide Žseglitide or MK678. SRIF analogs, whereas SRIF-2 receptors are insensitive to these compounds. In mammals, studies of receptor mRNA distribution and receptor protein localization have revealed a complicated expression pattern of sst receptors throughout the central nervous system and in a wide range of peripheral tissues, with an overlapping but differential pattern that is subtype-selective, tissue-specific, and species-specific ŽPatel, 1999.. All five types of sst receptors are expressed throughout brain; sst 1 is the predominant hypothalamic subtype ŽPatel, 1999.. In pituitary, all five types of sst receptors are expressed in the major cell types. Sst 5 and sst 2 are the principle subtypes expressed in the rat pituitary somatotrophes ŽKumar et al., 1997.. The physiological roles of each receptor subtype have been assessed with mammalian pituitary cells or transfected cells expressing each receptor subtype using subtype selective agonists, with selective antisense oligodeoxynucleotides to block the expression of each receptor gene, or with genetic animal models with selective deletion Žgene knock-out mice. of sst1 or sst2 receptor gene. Overall, these studies showed that sst 1 , sst 2 and sst 5 are involved in the inhibition of GH release ŽZheng et al., 1997; Rohrer et al., 1998; Parmar et al., 1999; Kreienkamp et al., 1999; Lanneau et al., 2000; Park et al., 2000. where sst 2 and sst 5 mediate inhibition of glucagon secretion and insulin secretion, respectively Žfor review, Benali et al., 2000.. In teleosts, the SRIF binding sites in brain have been characterized in goldfish ŽCardenas et al., 2000.. The characteristics of the SRIF binding sites have also been reported in liver membrane preparations and hepatocytes of rainbow trout ŽPesek et al., 1998; Pesek and Sheridan, 1996.. The distribution of the SRIF binding sites in brain has been reported in African lungfish ŽVallarino et al., 1997., an electric fish Apteronotus leptorhynchus, ŽZupanc et al., 1994. and goldfish ŽCardenas et al., 2000.. Overall, these studies show that SRIF-14 binding sites are widely dis-
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tributed throughout brain, with high density in the forebrain, optic tectum, and some regions of the hindbrain, suggesting multiple functions of SRIF-14 as a neurotransmitter andror a neuromodulator in fish. SRIF-14 binding sites have also been found on granulosa and theca cells of the ovary of an African lungfish ŽMasini et al., 1999., implicating SRIF in the control of ovarian function. Two type one SRIF receptor cDNAs were cloned from goldfish brain ŽLin et al., 1999b.. Both receptor mRNAs are widely distributed throughout goldfish brain, whereas only one receptor mRNA was detected in the pituitary. The two cDNAs share 92% similarity in nucleotide sequence and 98% similarity in the deduced amino acid sequences, and are presumably derived from duplicate genes, as goldfish are tetraploid. Two cDNAs encode two 367-amino acid goldfish type one SRIF receptors Žsst 1A and sst 1B ., which have 75᎐76% similarity to mammalian sst 1 , and 39᎐55% similarities to other mammalian sst subtypes Žsst 2 ᎐ 5 .. Both SRIF-14 and wPro 2 xSRIF14 significantly inhibited forskolin-stimulated cAMP release in COS-7 cells transiently expressing the cloned goldfish sst 1A or sst 1B receptors ŽLin et al., 1999b., suggesting coupling of the receptors to inhibition of adenylate cyclase. In addition, there were no apparent differences between two goldfish sst 1 receptors in their potencies for SRIF-14 and wPro 2 xSRIF-14, suggesting that two receptors display similar affinities for both peptides ŽLin et al., 1999b.. A type three sst receptor has been identified from Apteronotus albifrons ŽZupanc et al., 1999.. The Apteronotus sst 3 Žasst 3 . exhibits 56᎐59% sequence similarity with mammalian sst 3 . Expression of the sst 3 mRNA in brain was detected by RT-PCR. The pharmacological studies revealed that the fish sst 3 has a pharmacological profile compatible with that of mammalian SRIF-1 receptor group ŽSiehler et al., 1999.. Both SRIF-14 and mammalian SRIF-28 potently inhibited forskolin-stimulated adenylate cyclase activity in CCL39 cells expressing asst 3 receptors; this effect was blocked by pertussis toxin, suggesting coupling of the sst 3 receptor to Gi ␣ andror Go ␣ G-proteins ŽSiehler et al., 1999.. Radioligand binding studies were performed with four radioligands selective for mammalian SRIF receptors in CCL39 cells expressing the asst 3 receptors ŽSiehler et al., 1999.. w 125 I-Leu 8 , D-Trp 22 ,
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Tyr 25 xSRIF-28 Žmammalian SRIF-28 analog. and w 125 I-Tyr 10 xCST-14, and SRIF-14 analogs w 125 IxCGP 23996 and w 125 IxTyr 3-octreotide bind the cloned asst 3 receptors with high affinity. SRIF-14, mammalian SRIF-28, mammalian SRIF25 or rat cortistatin-14 displaced the radioligand binding on sst 3 with similar high affinity. However, catfish SRIF-22 exhibited low affinity for the sst 3 receptors. We have recently cloned a type two SRIF receptor from goldfish brain ŽLin et al., 2000.. The amino acid sequence of goldfish sst 2 has 61 and 62% similarity to human and rat sst 2 , respectively, and 41᎐47% similarities to other mammalian sst subtypes, and 42% similarity to both goldfish sst 1 receptors. The distribution and expression levels of the sst 2 receptor mRNA in brain regions and pituitary are different from the sst 1 receptor mRNAs. The sst 2 mRNA levels in pituitary are significantly higher than in brain regions, consistent with the findings in mammals that sst 2 and sst 5 are predominantly expressed in pituitary somatotrophs and involved in the direct regulation of GH secretion. The cloned sst 2 receptors are able to bind SRIF-14 and wPro 2 xSRIF14 and couple to inhibition of adenylate cyclase.
6. Concluding remarks SRIF-14 is conserved with identical primary structure in all classes of vertebrate. There is evidence for the expression of second andror third SRIF genes in a single vertebrate species, especially in the lower vertebrates. Three distinct SRIF genes have been identified in goldfish brain, making this species an ideal model for study of the SRIF gene family. Although our studies demonstrate that all three SRIF forms inhibit pituitary GH release in vitro ŽLin et al., 1999a, Chang and Peter, unpublished results, 2000., which SRIF is the primary neuroendocrine regulator of GH release in goldfish is not yet clear. Identification of multiple types of SRIF receptors raises a question whether a given physiological response is selective for one type of receptors or whether multiple types of receptors are involved. In addition, whether there is any particular link between a form of SRIF peptide and a receptor type is unknown. Overlapping expression of goldfish sst 1 and sst 2 receptors in pituitary and some brain regions implicates the involvement of multiple
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types of receptors in a physiological role of SRIF. Similarly, it has been proposed that sst may operate in concert, rather than as individual members in mammals, as individual target cells typically express multiple sst types ŽPatel, 1999.. Furthermore, a recent study demonstrated that human sst 5 can form agonist-dependent functional heterodimers with sst 1 but not with sst 4 , suggesting a direct molecular interaction between different sst subtypes ŽRocheville et al., 2000..
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