Pharmacological characterisation of the goldfish somatostatin sst5 receptor

doi:10.1016/S0014-2999(01)01626-0

European Journal of Pharmacology

Volume 436, Issue 3, 2 February 2002, Pages 173-186

https://doi.org/10.1016/S0014-2999(01)01626-0 Get rights and content

Abstract

Somatostatin (somatotropin release inhibiting factor, SRIF), exerts its effects via specific G protein coupled receptors of which five subtypes have been cloned (sst_1–5). Recently, SRIF receptors have also been cloned from fish tissues. In this study, goldfish sst₅ receptors (gfsst₅) were expressed and characterised in the Chinese hamster lung fibroblast cell line, that harbours the luciferase reporter gene driven by the serum responsive element (CCL39-SRE-Luci). The agonist radioligands [¹²⁵I]-LTT-SRIF-28 ([Leu⁸, dTrp²², ¹²⁵I-Tyr²⁵]SRIF-28) and [¹²⁵I][Tyr¹⁰]cortistatin-14 labelled similar receptor densities with high affinity and in a saturable manner (pK_d: 9.99–9.71; B_max: 300–350 fmol mg⁻¹). 5′-Guanylyl-imidodiphosphate inhibited radioligand binding to some degree (38.5–57.9%). In competition binding studies, the pharmacological profile of SRIF binding sites defined with [¹²⁵I]LTT-SRIF-28 and [¹²⁵I][Tyr¹⁰]cortistatin-14 correlated significantly (r²=0.97, n=20). Pharmacological profiles of human and mouse sst₅ receptors expressed in CCL39 cells correlated markedly less with those of the gfsst₅ profile (r²=0.52–0.78, n≥16). Functional expression of the gfsst₅ receptor was examined by measurement of agonist-induced luciferase expression and stimulation of [³⁵S]GTPγS ([³⁵S]guanosine 5′-O-(3-thiotriphosphate) binding. Profiles were similar to those achieved in radioligand binding studies (r²=0.81–0.93, n=20), although relative potency (pEC₅₀) was reduced compared to pK_d values. Relative efficacy profiles of luciferase expression and [³⁵S]GTPγS binding, were rather divergent (r²=0.48, n=20) with peptides showing full agonism at one pathway and absence of agonism at the other. BIM 23056 (d-Phe-Phe-Tyr-d-Trp-Lys-Val-Phe-d-Nal-NH₂) acted as an antagonist on the effects of SRIF-14 (pK_B=6.74±0.23) on stimulation of [³⁵S]GTPγS binding. Pertussis toxin abolished the effect of SRIF-14 on luciferase expression and [³⁵S]GTPγS binding suggesting coupling of the receptor to G_i/G_o proteins. In summary, the present studies demonstrate that the gfsst₅ receptor has a similar pharmacological profile and transductional properties to mammalian sst₅ receptors. The difference in efficacy profiles defined using different functional assays suggests numerous, agonist specific, conformational receptor states, and/or ligand-dependent receptor trafficking.

Introduction

Somatostatin or SRIF (somatotropin release inhibiting factor) is a hormone/neuropeptide which is found at high levels in the central and peripheral nervous system, and a number of peripheral tissues. It is involved in the regulation of multiple physiological processes, including endocrine and exocrine secretions, neurotransmission, neuromodulation of transmitter release, smooth muscle motility and cell proliferation, especially in tumours Reichlin, 1983, Patel, 1997.

In mammals, SRIF is found in two forms—SRIF-14, and the N-terminally extended SRIF-28. These two peptides are produced from a single gene which encodes preprosomatostatin (PSS); this is differentially cleaved to either SRIF-14 or SRIF-28 Pradayrol et al., 1980, Patel and O'Neil, 1988, Patel and Galanopoulou, 1995. SRIF-14 is highly conserved throughout evolution, being found in all mammalian species studied and in representatives from all vertebrate classes including birds, amphibians, reptiles and fish (Lin et al., 2000b). Although rare, variants of SRIF-14 are also found in some species including [Ser¹²]SRIF-14 in Sea Lamprey (Andrews et al., 1988), [Ser⁵]SRIF-14 in Pacific Ratfish (Conlon, 1990), [Pro²,Met¹³]SRIF-14 in European Green Frog (Vaudry et al., 1992) and [Pro²]SRIF-14 in Russian Sturgeon, African Lungfish and Goldfish Nishii et al., 1995, Lin et al., 1999b, Trabucchi et al., 1999.

Recently, it has been shown that SRIF is part of a multigene family. A second SRIF precursor gene (PSS-II) has been identified in teleost fish, that is processed to SRIF peptides of 28, 25, or 14 amino acids in length with [Tyr⁷,Gly¹⁰]SRIF-14 (or a variant of this depending on the species) at their C terminus Conlon et al., 1987, Zupanc et al., 1999, Lin et al., 2000b. In frog brain, a second PSS gene has been identified which is processed to [Pro²,Met¹³]SRIF-14 (Vaudry et al., 1992). A prepropeptide cDNA with structural similarity to that of preprosomatostatin has also been cloned in mammals. This is cleaved to produce cortistatin which is found in rat, mouse and human brain in various forms and has a 14 amino acid peptide at its C-terminus with 11 amino acids identical to SRIF-14 De Lecea et al., 1996, De Lecea et al., 1997, Fukusumi et al., 1997. Goldfish have three distinct SRIF precursor genes. These are termed PSS-I, PSS-II and PSS-III and are processed to SRIF-14, goldfish SRIF-28 which has [Glu¹, Tyr⁷, Gly¹⁰]SRIF-14 at its C terminus, and [Pro²]SRIF-14, respectively Lin et al., 1999b, Lin et al., 2000b.

SRIF produces its effects by binding to high affinity membrane bound G protein-coupled receptors Schonbrunn and Tashjian, 1978, Jakobs et al., 1983, Bell and Reisine, 1993 of which five subtypes (sst_1–5) have been identified from several mammalian species Bell and Reisine, 1993, Hoyer et al., 1994, Hoyer et al., 1995. The receptors display a subtype-specific distribution pattern in brain and peripheral tissues Bell and Reisine, 1993, Patel, 1997, Selmer et al., 2000. All five receptor subtypes bind SRIF-14 and SRIF-28 with high affinity, but differ in their ability to bind the short-chain synthetic analogues octreotide, seglitide and somatuline, producing two distinct subclasses according to pharmacology and structure: sst_2, sst_{3 and} sst₅, with high affinity for the short analogues and sst_{1 and 4}, with low affinity (Hoyer et al., 1995).

In goldfish, cDNAs for two receptors corresponding to mammalian sst₁, one corresponding to mammalian sst₂ and one to mammalian sst₅ have been cloned (Lin et al., 1999a, Lin et al., 2000a; submitted). The sst₁ receptors (termed sst_1A and sst_1B) have 98% homology in their amino acid sequences and are thought to be the product of duplicate genes rather than spliced variants (Lin et al., 1999a). An sst₃ subtype (fsst₃) has been isolated in an electric fish Apteronotus albifrons Siehler et al., 1999b, Zupanc et al., 1999.

In the present study, the newly cloned goldfish sst₅ (gfsst₅) receptor (Lin et al., 2002, in press) was expressed in Chinese hamster lung fibroblast cells (CCL39), and its pharmacological features examined and compared to those of human and mouse sst₅ using radioligand binding studies, and stimulation of [³⁵S]guanosine 5′-O-(3-thiotriphosphate ([³⁵S]GTPγS) binding and coupling via the serum responsive element to luciferase expression.

Section snippets

Cell culture

CCL39-SRE-Luci cells (established line of Chinese hamster lung fibroblasts; American Type Culture Collection), were cultured in a 1:1 mixture of Dulbecco's Modified Eagle's Medium (DMEM; Seromed, Biochrom, Berlin, Germany: 3.7 g l⁻¹ NaHCO₃, 1.0 g l⁻¹ d-glucose, with stable glutamine) and Ham's F-12 Nutrient Mixture (Seromed: 1.176 g l⁻¹ NaHCO₃, with stable glutamine), supplemented with 10% (v/v) foetal bovine serum (Gibco BRL) and Hygromycin B (100 μg ml⁻¹) (Calbiochem, La Jolla, CA, USA) at 37

Radioligand binding

[¹²⁵I]LTT-SRIF-28 and [¹²⁵I][Tyr¹⁰]cortistatin-14 labelled gfsst₅ binding sites in CCL39-SRE-Luci cells with high affinity and in a saturable manner ([¹²⁵I]LTT-SRIF-28: B_max=303±15 fmol mg⁻¹, pK_d=9.99±0.19; [¹²⁵I][Tyr¹⁰]cortistatin-14: B_max=348±23 fmol mg⁻¹, pK_d=9.71±0.08) (Fig. 1). There was no significant difference between the sites labelled by the two radioligands (Data analysed using independent t-tests, P: 0.227 and 0.150; n=4 for pK_d and B_max, respectively). Non-specific binding was

Discussion

The somatostatin neuropeptide family exerts its effects by binding to G protein-coupled receptors of which five subtypes have been cloned from several mammalian species and sst_1A, sst_1B, sst₂, sst₃ and sst₅ receptors have been cloned from teleost fish species (Bell and Reisine, 1993, Hoyer et al., 1994, Hoyer et al., 1995, Siehler et al., 1999b, Lin et al., 2002). In this study, a type 5 somatostatin receptor isolated from goldfish has been expressed and pharmacologically characterised in

Acknowledgements

Work supported in part by EC Contract QLG3-CT-1999-00908 and Swiss grant BBW 00-0427.

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Somatostatin (SRIF) modulates neurotransmitter release by activating the specific receptors (sst₁-sst₅). Our previous study showed that sst₅ receptors are expressed in rat retinal GABAergic amacrine cells. Here, we investigated modulation of GABA release by SRIF in cultured amacrine cells, using patch-clamp techniques. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in the amacrine cells was significantly reduced by SRIF, which was partially reversed by BIM 23056, an sst₅ receptor antagonist, and was further rescued by addition of CYN-154806, an sst₂ receptor antagonist. Both nimodipine, an L-type Ca²⁺ channel blocker, and ω-conotoxin GVIA, an N-type Ca²⁺ channel blocker, suppressed the sIPSC frequency, and in the presence of nimodipine and ω-conotoxin GVIA, SRIF failed to further suppress the sIPSC frequency. Extracellular application of forskolin, an activator of adenylate cyclase, increased the sIPSC frequency, while the membrane permeable protein kinase A (PKA) inhibitor Rp-cAMP reduced it, and in the presence of Rp-cAMP, SRIF did not change sIPSCs. However, SRIF persisted to suppress the sIPSCs in the presence of KT5823, a protein kinase G (PKG) inhibitor. Moreover, pre-incubation with Bis IV, a protein kinase C (PKC) inhibitor, or pre-application of xestospongin C, an inositol 1,4,5-trisphosphate receptor (IP₃R) inhibitor, SRIF still suppressed the sIPSC frequency. All these results suggest that SRIF suppresses GABA release from the amacrine cells by inhibiting presynaptic Ca²⁺ channels, in part through activating sst₅/sst₂ receptors, a process that is mediated by the intracellular cAMP–PKA signaling pathway.
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Consistent with the present study, we obtained preliminary data using a calcium mobilization assay that barfin flounder MCHR1 and MCHR2 have the same G protein-coupling system as goldfish receptors. To the best of our knowledge regarding studies on heterologous protein-expressing cells, MCHRs may be the first example of such a difference in peptide receptor-mediated signalling pathways between mammals and teleosts fish [43–45]. This observed feature of MCHRs is of particular interest, and may indicate that the MCHR-G protein interactions have changed during evolution from fish species to humans.
Melanin-concentrating hormone (MCH) is the natural ligand for the MCH-1 receptor (MCHR1) and MCH-2 receptor (MCHR2). The MCH–MCHR1 system plays a central role in energy metabolism in rodents. Recently, we identified MCHR1 and MCHR2 orthologues in goldfish, designated gfMCHR1 and gfMCHR2. In a mammalian cell-based assay, calcium mobilization was evoked by gfMCHR2 via both Gαi/o and Gαq, while the gfMCHR1-mediated response was exclusively dependent on Gαq. This coupling capacity to G proteins is in contrast to human MCHR1 and MCHR2. Here, we extended our previous characterization of the two gfMCHRs by examining their different signalling pathway. We found that MCH caused activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) via both gfMCHR1 and gfMCHR2 in dose-dependent manners. Unlike the case for gfMCHR2, gfMCHR1 signalling was not sensitive to pertussis toxin, suggesting Gαq coupling of gfMCHR1 in the ERK1/2 pathway as well as a calcium mobilization system. Cyclic AMP assays revealed that gfMCHR2 was efficiently coupled to Gαi/o, while gfMCHR1 was weakly coupled to Gαs. Finally, we investigated the transduction features stimulated by two mammalian MCH analogues. As expected, Compound 15, which is a full agonist of human MCHR1, was a potent gfMCHR1 agonist in multiple signalling pathways. On the other hand, Compound 30, which is a human MCHR1-selective antagonist with negligible agonist potency, unexpectedly acted as a selective agonist of gfMCHR1. These results are the first to demonstrate that gfMCHR1 and gfMCHR2 have quite different signalling properties from human MCHRs.
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How these different inhibitory actions of SS-14 and gbSS-28 are manifested is unknown but the use of different SS receptor subtypes (Ssts) is a distinct possibility. For instance, SS-14 activation of goldfish Sst2 results in decreases in cAMP via Gi protein, whereas gbSS-28 attenuates cAMP formation via binding to Sst5 rather than Sst2 (Lin et al., 2000; Nunn et al., 2002). Interestingly, Sst signalling in mammals can also be altered as a consequence of these receptors physically interacting with other families of G-protein-coupled receptors, including DA receptors (Duran-Prado et al., 2008).
Dopamine (DA) and pituitary adenylate cyclase-activating polypeptide (PACAP) stimulate goldfish growth hormone (GH) release via cAMP- and Ca²⁺-dependent pathways while DA also utilizes NO. In this study, identified goldfish somatotropes responded to sequential applications of PACAP and the DA D1 agonist SKF38393 with increased intracellular Ca²⁺ levels ([Ca²⁺]_i), indicating that PACAP and DA D1 receptors were present on the same cell. A native goldfish brain somatostatin (gbSS-28) reduced SKF38393-stimulated cAMP production and PACAP- and NO donor-elicited GH and [Ca²⁺]_i increases, but not PACAP-induced cAMP production nor the GH and [Ca²⁺]_i responses to forskolin, 8-bromo-cAMP and SKF38393. gbSS-28 might inhibit PACAP-induced GH release by interfering with PACAP's ability to increase [Ca²⁺]_i in a non-cAMP-dependent manner. However, DA D1 receptor activation bypassed gbSS-28 inhibitory effects on cAMP production and NO actions via unknown mechanisms to maintain a normal [Ca²⁺]_i response leading to unhampered GH release.
Involvement of protein kinase C and intracellular Ca<sup>2+</sup> in goldfish brain somatostatin-28 inhibitory action on growth hormone release in goldfish
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SS-14 and [Pro2]SS-14 bind goldfish Sst2s expressed in COS-7 cells with similar affinity and exhibit similar potency in inhibiting adenylate cyclase. On the other hand, gbSS-28 has no effect on forskolin-stimulated cAMP production in COS-7 cells expressing Sst2s but the gbSS-28-selective Sst5s expressed in CCL39 cells are coupled to Gi/o-protein (Lin et al., 2000; Nunn et al., 2002). Interestingly, gbSS-28 is the most potent among the three goldfish SSs in suppressing basal GH secretion, but it is less effective than SS-14 in inhibiting GnRH-induced GH release in static incubation of dispersed goldfish pituitary cells (Yunker et al., 2003).
Goldfish brain somatostatin-28 (gbSS-28) is present in brain and pituitary tissues of goldfish. We assessed whether gbSS-28 targets Ca²⁺ and/or protein kinase C (PKC)-dependent signaling cascades in inhibiting growth hormone (GH) release. gbSS-28 decreased basal GH release from primary cultures of dispersed goldfish pituitary cells and intracellular free calcium levels ([Ca²⁺]_i) in goldfish somatotropes. gbSS-28 partially reduced [Ca²⁺]_i and GH responses induced by two endogeneous gonadotropin-releasing hormones (GnRHs), salmon (s)GnRH and chicken (c)GnRH-II. Furthermore, gbSS-28 reduced GH increases and abolished [Ca²⁺]_i elevations elicited by two PKC activators, tetradecanoyl 4β-phorbol-13-acetate and dioctanyl glycerol. The PKC inhibitors Gö6976 and Bis II abolished [Ca²⁺]_i responses to PKC activators, but only attenuated GnRH-induced increases in [Ca²⁺]_i and did not alter basal [Ca²⁺]_i. In cells pretreated with Bis II, gbSS-28 further reduced basal [Ca²⁺]_i. Our results suggest that gbSS-28 inhibits GnRH-induced GH release in part by attenuating PKC-mediated GnRH [Ca²⁺]_i signals. gbSS-28 reduces basal GH release also via reduction in [Ca²⁺]_i but PKC is not involved in this regard.
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As in mammals, fish possess multiple SSTR subtypes; to date four distinct subtypes have been characterized (SSTR 1–3 and 5) (Volkoff et al., 2005; Klein and Sheridan, 2008). Ligand-selective binding characteristics have been reported for some SSTRs of trout and goldfish (Nunn et al., 2002; Gong et al., 2004; Siehler et al., 2008). Knowledge of the mechanisms of SS action in fish is limited; however, cAMP, Ca2+/PKC, ERK, and PI3K/Akt appear to be involved (Yunker and Chang, 2001, 2004; Hagemeister and Sheridan, 2008).
Multiple forms of somatostatin (SS) and SS receptors (SSTR) are produced widely in the tissues of fish and interact to coordinate numerous physiological processes. Insight into their role in growth regulation emerged from studies of abnormal growth and of whole animals. The influence of SS on organismal growth operates at several levels of the growth hormone (GH)–insulin-like growth factor-1 (IGF-1) system. SS inhibits production and release of pituitary GH, but not all forms of SS are equipotent in this action. SS also influences the GH–IGF-1 system in an extrapituitary manner by reducing sensitivity to GH as well as by inhibiting IGF-1 production and secretion, and diminishing IGF-1 sensitivity. Peripheral actions of SS are important for the local control of growth and may help to coordinate growth with other processes such as metabolism, development, and reproduction by reprogramming cell responsiveness.
Pharmacological profile of somatostatin and cortistatin receptors
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Somatostatin (SRIF) and cortistatin (CST) are two endogenous peptides with high sequence similarities that act as hormones/neurotransmitters both in the CNS and the periphery; their genes although distinct result from gene duplication. Their receptors appear to be common, since the five known SRIF receptors (sst1–sst5) have similar subnanomolar affinity for SRIF and CST, whether the short (SRIF-14, CST-14, CST-17) or the long versions (SRIF-28, CST-29) of the peptides. Whether CST targets specific receptors not shared by SRIF, is still debated: MrgX2 has been described as a selective CST receptor, with submicromolar affinity for CST but devoid of affinity for SRIF; however the distribution of CST and MrgX2 is largely different, and there is no MrgX2 in rodents. A similar situation arises with the GHS receptor GHS-R1a, which displays some preferential affinity for CST over SRIF, but for which there is no evidence that it is activated by CST in vivo. In both cases, one may argue that submicromolar affinity is not the norm of a GPCR for its endogenous neuropeptide. On the other hand, all receptors known to bind SRIF have similar high affinity for CST and both peptides act as potent agonists at the sst1–sst5 receptors, whichever transduction pathway is considered. In addition, [¹²⁵I][Tyr¹⁰]CST₁₄ labels sst1–sst5 receptors with subnanomolar affinity, and [¹²⁵I][Tyr¹⁰]CST₁₄ binding in the brain is overlapping with that of [¹²⁵I][Tyr⁰]SRIF₁₄. The functional differences reported that distinguish CST from SRIF, have not been explained convincingly and may relate to ligand-driven transductional selectivity, and other complicating factors such as receptor dimerisation, (homo or heterodimerisation), and/or the influence of accessory proteins (GIPs, RAMPS), which remain to be studied in more detail.

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Pharmacological characterisation of the goldfish somatostatin sst5 receptor

Abstract

Introduction

Section snippets

Cell culture

Radioligand binding

Discussion

Acknowledgements

J. Biol. Chem.

Trends Neurosci.

Anal. Biochem.

Gen. Comp. Endocrinol.

Eur. J. Pharmacol.

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