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Functional Association of Somatostatin Receptor Subtypes 2 and 5 in Inhibiting Human Growth Hormone Secretion

Cedars-Sinai Research Institute (S.-G.R., R.Y., S.M.), University of California, Los Angeles, School of Medicine, Los Angeles, California 90048; and Biomeasure Inc. (J.T., J.D., M.D.C.), Milford, Massachusetts 01757

Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048. E-mail: melmed{at}cshs.org.

	Abstract

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We previously demonstrated that somatostatin (SRIF)-induced inhibition of GH secretion from human pituitary cells is mediated through both the SRIF receptor (SSTR) 2 and 5 subtypes. The interplay between these two SSTR subtypes in regulating GH was therefore tested in primary human fetal pituitary cultures (18–30 wk gestation). GHRH (10 nM)-stimulated GH secretion (51% increase, P < 0.05) was suppressed equally by either SSTR2 or SSTR5-selective agonists (10 nM). GH suppression correlated with agonist affinity for their respective receptor subtypes. Combined addition of SSTR2- and SSTR5-specific agonists was synergistic for GH suppression, achieving 73% (P < 0.05) inhibition as compared with inhibition attained with SSTR2 (32%) and SSTR5 (34%) agonists used alone (P < 0.05). The SSTR2 selective antagonist BIM-23454 dose-dependently blocked SSTR2 but not SSTR5-induced suppression of GH secretion. BIM-23454 also completely reversed GH suppression in response to the combined activation of SSTR2 and SSTR5. The IC₅₀ for BIM-23454 reversal of agonist-induced GH suppression was 55 nM and 33 nM for two SSTR2 agonists, 45 nM and 40 nM for the combination of SSTR2 and SSTR5 agonists, respectively, and 45 nM for the SSTR2/SSTR5 agonist BIM-23244, all of which were similar to the affinity of BIM-23454 for SSTR2 (32 nM). These results suggest the following: 1) activation of both SSTR2 and SSTR5 induces a functional association of receptor subtypes, resulting in synergistic GH suppression; 2) BIM-23454 is a potent SSTR2-selective antagonist capable of reversing SRIF-induced GH suppression; and 3) the ability of a selective SSTR2 antagonist to inhibit the GH suppressing action of SSTR2 agonist alone, SSTR2/SSTR5 biselective agonists, or SSTR2 and SSTR5 agonists in combination support the concept of a functional interaction between somatotroph SSTR2 and SSTR5 subtypes in primary human fetal pituitary cells.

	Introduction

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NATIVE SOMATOSTATIN (SRIF) is widely distributed throughout the central nervous and peripheral tissues and exerts a variety of physiological effects through binding to specific cell surface SRIF receptors (SSTRs) (1, 2, 3, 4). In the anterior pituitary, SRIF serves as a suppressor of hormone secretion, particularly of GH. Using SSTR subtype-selective SRIF agonists, we previously showed that in human pituitary adenomas, both SSTR2 and SSTR5 selective agonists suppress GH secretion, but only SSTR5-selective agonists inhibit prolactin (PRL) secretion. In human fetal pituitary cells, however, PRL suppression is mediated mainly by SSTR2, and GH is suppressed by both SSTR2 and SSTR5 (5, 6).

Patients harboring GH-secreting tumors that express high receptor density with a high affinity for octreotide have the most favorable in vivo GH responses to octreotide treatment (7). Combination of SSTR2- and SSTR5-preferring agonists and a SSTR2/SSTR5 biselective agonist enhance the efficacy of GH suppression from octreotide-resistant GH-secreting adenomas (8). This report and our prior observations suggest an interaction between SSTR2 and SSTR5 in GH regulation.

A novel SRIF antagonist, BIM-23454 (9), which functions as an antagonist at SSTR2 and a weak agonist at SSTR5, and other SRIF antagonists were recently demonstrated to increase basal GH, insulin, and glucagon release and reverse SRIF-mediated suppression of GH, insulin, and glucagon secretion in intact rats (10, 11). Using this SSTR2-selective antagonist, and newly developed agonists that are highly selective for SSTR2 and SSTR5, we tested the requirement for SSTR2 in the interaction of SSTR2 and -5 in suppression of GH secretion from the human pituitary.

	Materials and Methods

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Somatostatin agonists and antagonists

BIM-23120, BIM-23197, BIM-23206, BIM-23268, BN82087, BIM-23244, BIM-23454, and BIM-23867 were obtained from Biomeasure Inc. (Milford, MA). Specific binding affinities of these compounds for different human SSTRs were determined by radioligand membrane receptor-binding assays as previously described (5). According to the binding assays (Table 1), these compounds can be classified as SSTR2-preferring (BIM-23197); SSTR5-preferring (BIM-23268); SSTR2-selective (BIM-23120); SSTR5-selective (BIM-23206 and BN82087); SSTR2 and -5 biselective (BIM-23244) agonists; and SSTR2-selective (BIM-23454) antagonists. Stock solutions (100 µM) of the peptide agonists and antagonists were prepared in 0.01 M acetic acid and 0.1% BSA, and stored at -20 C until used. Stock solutions (5 mM) of the nonpeptide, BN82087 were prepared in saline containing 10% dimethylsulfoxide, and stored at 4 C until used.

Tissue collection from a third-party clinic was approved by the Institutional Review Board and obtained after informed consent. Twenty fetal pituitary specimens of gestational age 18–30 wk and both sexes were obtained within 0.5–2 h of a termination procedure. Pituitary cell preparations were previously described (5, 6, 12). Briefly, the pituitary was washed, minced, and enzymatically dissociated in DMEM medium containing 0.35% collagenase, 0.15% hyaluronidase, and 0.3% BSA (all three from Sigma, St. Louis, MO) at 37 C for 45 min. The enzymatic dissociation was terminated by adding DMEM with 10% fetal bovine serum, and the cell suspensions filtered, centrifuged, and resuspended in DMEM with 10% fetal bovine serum and antibiotics, followed by incubation in 48-multiwell tissue culture plates for 72 h. Cells were treated for an additional 4–6 h in 0.3% BSA DMEM with or without GHRH (Peninsula Laboratories Inc., Belmont, CA), SRIF agonists, or antagonists, as indicated. At the end of the treatment, medium was collected and stored at -20 C until GH assay (Diagnostic Products Corp., Los Angeles, CA).

Statistical analysis

Data are represented as mean ± SEM. Hormone level changes are expressed as a percentage of mean control in the same experiment. Differences between groups were determined by t test and correlation coefficients determined by linear regression analysis. The maximal inhibitory effect of the SRIF agonists on GH secretion (100% of inhibitory effect) was achieved at doses of 10 nM (5). The inhibitory effect was reversed (decreased) with increasing doses of the antagonists. The reversal curves were fit to a logarithmic equation using the Crick program, from which IC₅₀ was calculated.

	Results

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Correlation between GH suppression and affinity of SRIF agonists for their respective subtype

Primary fetal pituitary cell cultures responded to 10 nM GHRH, resulting in increased GH secretion by 151 ± 7% (P < 0.05). GHRH-stimulated GH secretion was suppressed equally by either SSTR2 or SSTR5 agonists at doses of 10 nM (Fig. 1), confirming our previous observation that GH inhibition by SRIF in the human pituitary is mediated through both SSTR2 and SSTR5.

View larger version (15K): [in this window] [in a new window]   FIG. 1. Comparison of SSTR2 and SSTR5 agonists, either alone or in combination, in suppressing GH secretion. Human fetal pituitaries were collected at 18–30 wk gestation. After digestion, pituitary cells were preincubated for 72 h and then exposed to GHRH (10 nM) with or without (control group) SRIF analogs (10 nM) in 0.3% BSA serum-free medium for an additional 4–6 h. Each bar represents mean ± SEM. GH suppression as a percentage of controls in 20–48 wells from five to six experiments. SSTR2 and SSTR5 affinity were derived from Table 1. *, P < 0.05, compared with controls; #, P < 0.05, compared with analog used alone. (97: BIM-23197; 68: BIM-23268; 20: BIM-23120; 06: BIM-23206; 44: BIM-23244).

View larger version (12K): [in this window] [in a new window]   FIG. 2. Correlation between GH suppression and binding affinity of analogs used. Data used for calculation in this figure was obtained from the experiments indicated in Fig. 1.

The SSTR2-specific agonist BIM-23120 or SSTR5-specific agonist BIM-23206, tested individually, suppressed GHRH-stimulated GH secretion by 32 ± 2% and 34 ± 2%, respectively, compared with GHRH alone (P < 0.05). The combination of these two agonists, however, acted synergistically to suppress GH secretion (73 ± 7%, P < 0.05, compared with single analog use). The SSTR2-preferring agonist, BIM-23197, which also possesses moderate affinity for SSTR5, suppressed GH by 39 ± 4%. Similarly, the SSTR5-preferring agonist, BIM-23268, which also possesses SSTR2 affinity, suppressed GH by 47%. When BIM-23197 and BIM-23268 were combined, GH was suppressed by 55 ± 6% (P < 0.05, compared with BIM-23197 alone). The SSTR2/SSTR5-biselective agonist, BIM-23244, suppressed GH secretion by 64 ± 6% (P < 0.05). These results (Fig. 1) demonstrate the synergy between SSTR2 and SSTR5 in suppressing GH secretion.

Characterization of the SSTR2 antagonist, BIM-23454

In human recombinant SSTR2 receptor-transfected Chinese hamster ovary (CHO) cells, BIM-23454 dose-dependently reversed SRIF-14-stimulated intracellular calcium mobilization. SRIF-induced calcium mobilization was completely blocked by BIM-23454 at a concentration of 100 nM as shown in Fig. 3A. As expected, and similar to native SRIF, the SSTR2 agonists, BIM-23120 and BIM-23197, also dose-dependently stimulated intracellular calcium mobilization, but the SSTR2-antagonist, BIM-23454, did not (Fig. 3B). In human recombinant SSTR5 receptor-transfected CHO cells, 1000 nM BIM-23454-stimulated intracellular calcium mobilization to an extent similar to that induced by 1 nM SSTR5 agonists, as shown in Fig. 3C. These results suggest that BIM-23454 functions as an antagonist for SSTR2 and a very weak agonist for SSTR5.

View larger version (17K): [in this window] [in a new window]   FIG. 3. Characterization of the SSTR2 antagonist, BIM-23454. Human SSTR2 receptor (A, B) or SSTR5 receptor (C) were transfected into CHO K1 cells. After treatment with SRIF agonists or antagonist, intracellular calcium mobilization was measured. In this model system, SSTR2 and -5 agonists increase intracellular calcium mobilization in cells expressing the appropriate SSTR subtype, and BIM-23454 antagonism inhibits agonist-induced calcium mobilization. A, BIM-23454 dose-dependently suppresses SRIF-14 (10 nM)-induced mobilization of calcium in SSTR2-expressing cells. B, C, Calcium mobilization induced by BIM-23454 and SSTR2 and -5 selective agonists in SSTR2- and SSTR-5 transfected cells.

Ability of the SSTR2 antagonist, BIM-23454, to reverse GH suppression induced by SSTR2 and/or SSTR5 agonists

SSTR2 agonist (BIM-23197 or BIM-23120, 10 nM)-induced GH suppression was completely reversed by BIM-23454 at a concentration of 200 nM. However, at the same concentration, the antagonist was unable to reverse SSTR5-specific agonist (BIM-23206, 10 nM)-induced GH suppression (Fig. 4). The nonpeptide SSTR5-selective agonist, BN82087, at 1, 10, and 100 nM, inhibited GH secretion from fetal pituitary cells by 8 ± 0.7%, 46 ± 4%, and 67 ± 5%, respectively. BIM-23454, at a concentration of 300 nM, did not block BN82087 (100 nM)-induced GH suppression (Fig. 4). These results demonstrate that BIM-23454 is a potent SSTR2-specific antagonist, capable of reversing SSTR2 but not SSTR5-induced GH suppression.

View larger version (33K): [in this window] [in a new window]   FIG. 4. Inhibitory effects of the SSTR2 antagonist, BIM-23454, on GH suppression induced by SSTR2 and SSTR5 agonists. Fetal pituitary cells were preincubated for 72 h and then exposed to either SSTR2 agonists or SSTR5 agonists, either with or without BIM-23454 (200–300 nM) for 4–6 h. Each bar represents mean ± SEM of 8–48 wells in two to six experiments. *, P < 0.05 vs. control.

View larger version (22K): [in this window] [in a new window]   FIG. 5. Dose-dependent reversal of SSTR agonist-induced GH suppression by the SSTR2 antagonist, BIM-23454 (A). Fetal pituitary cells were preincubated for 72 h and then exposed to the SSTR2-selective agonist BIM-23120 (10 nM), the SSTR5 agonist BIM-23206 (10 nM), or a combination of BIM-23120 and BIM-23206 (10 nM each) in serum-free medium with10 nM GHRH and varying doses (0–400 nM) of the SSTR2 antagonist BIM-23454 for 4–6 h. Each point represents mean percent inhibition of GH secretion in 8–14 wells from two to three experiments.

When BIM-23206 and BIM-23120 (10 nM) were combined (Fig. 5), the concentration of GH was reduced to 34% of that observed in vehicle-treated control cultures. Addition of BIM-23454 (25, 50, 100, and 200 nM) dose-dependently reversed the BIM-23120+BIM-23206 combination-induced GH inhibition (60%, 65%, 92%, and 100% of vehicle-treated control cultures, respectively). The concentration of BIM-23454 required to achieve 50% reversal effect of the combined BIM-23120 + BIM-23206 effect was 45 nM, which approximated the Ki of BIM-23454 for SSTR2 and was similar to the concentration required to achieve 50% reversal of BIM-23120 alone.

Similar results were observed for BIM-23454 reversal of the suppression of GHRH-stimulated GH secretion achieved with the potent, biselective SSTR2 + 5 agonist, BIM-23244; the SSTR2-preferring BIM-23197, which also possesses moderate SSTR5 activity; the SSTR5-preferring BIM-23268, which also possesses moderate SSTR2 activity; and the combination of BIM-23197 and BIM-23268. The concentration of BIM-23454 required to achieve 50% reversal of GH inhibition was 45 nM for BIM23244, 33 nM for BIM23197, 35 nM for BIM23268, and 40 nM for the combination of BIM-23197 and BIM-23268 (Fig. 6), all of which approached the Ki of BIM-23454 for SSTR2 (Table 1).

View larger version (24K): [in this window] [in a new window]   FIG. 6. Dose-dependent reversal of SSTR agonist-induced GH suppression by the SSTR2 antagonist, BIM-23454 (B). Fetal pituitary cells were preincubated for 72 h and then exposed to the SSTR2-preferring agonist BIM-23197 (10 nM), the SSTR5-preferring agonist BIM-23268 (10 nM), a combination of BIM-23197 and BIM-23268 (10 nM each), or the SSTR2/SSTR5 biselective agonist BIM-23244 (10 nM) in serum-free medium with 10 nM GHRH and varying doses (0–200 nM) of the SSTR2 antagonist BIM23454 for 4–6 h. Each point represents the mean percentage inhibitory effect on GH secretion in 8–14 wells from two to three experiments.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

The efficacy of SRIF agonists in inhibiting GH secretion depends on the expression of specific SSTR subtypes by target cells (1, 7, 13, 14). All five SSTR subtypes are expressed in the pituitary (1, 4, 15, 16, 17, 18, 19), with SSTR2 and SSTR5 being the most abundant in GH-secreting cells (4, 15, 20). By 18–30 wk of gestation, human fetal pituitaries already express mature SSTR subtypes and hormone-producing cells (5). The functional consequence of these observations is that both SSTR2 and -5 likely participate in SRIF-mediated GH suppression in the human pituitary.

The functional efficacy of SSTR agonists in suppressing GH secretion also depends on the affinity of these agonists for their respective receptor subtype(s). At a concentration of 10 nM, which showed maximal GH inhibition in a previous study (5), BIM-23120 is an SSTR2-selective agonist, as is BIM-23206, a selective agonist for SSTR5 (Table 1), whereas BIM-23197 is SSTR2 preferring, with moderate activity at SSTR5, as is BIM-23268 SSTR5 preferring, with moderate SSTR2 activity. When these agonists were ranked according to their affinities at both SSTR2 and -5, a significant correlation between affinity and GH suppression was observed, further indicating that it is the combined activity at SSTR2 and -5 that ultimately confers efficacy in suppressing GH secretion.

Our results have shown BIM-23454 to be an SSTR2 subtype-selective antagonist (Figs. 3 and 4). In the presence of BIM-23454, SSTR5 agonists retain their ability to activate SSTR5 (Fig. 4). The observed effect was not the result of BIM-23454 functioning as a weak SSTR5 agonist because BIM-23454 at 400 nM exhibits only 0.1–1% of the GH suppressing activity of the selective SSTR5 agonist, BIM-23206, at a dose of 10 nM (Fig. 3C). These results suggest that SSTR2 is not necessary for SSTR5 function in suppressing GH secretion from the normal pituitary. This observation in human fetal pituitary differs from that observed in acromegaly patients, in which SSTR2 levels, but not SSTR5, directly relate to the degree of GH suppression by SRIF (14), perhaps reflecting a functional distinction of SSTR subtypes in tumor cell types. Our previous studies showed that PRL suppression by SRIF in human pituitary adenomas is mediated primarily through SSTR5. In the fetal pituitary, however, PRL suppression is through SSTR2 (5, 6). Whether a mutation of SSTR5 occurs in the adenoma remains unresolved.

Ligand activation of a particular SSTR subtype by SRIF is associated with either a reduction of intracellular cAMP or calcium concentrations or stimulation of protein tyrosine phosphatase, depending on the receptor-coupled signaling pathway (1, 4). In mouse pancreas, SSTR2 inhibits glucagon release, and SSTR5 is a mediator of insulin (21). SSTR2-signaling pathway may differ in part from SSTR5 (1). SRIF agonists inhibit cell proliferation via SSTR2 and SSTR5 through different mechanisms (22). In human neuroblastoma cells, SSTR2 and SSTR5 have different effects on Ras/MAPK pathway and cell proliferation (23). The observed synergy between SSTR2 and -5 in suppressing GH secretion provides functional evidence that SSTR2 and -5 actions may be mediated through different pathways in normal human pituitary.

The present study demonstrates that the GH suppression induced by either SSTR2 and SSTR5 agonists in combination or SSTR2/SSTR5 biselective-induced agonists is completely reversed by an SSTR2-selective antagonist. This finding suggests at least a functional, if not physical, association between SSTR2 and SSTR5 when the two receptors are activated. Recent studies have demonstrated that when cells cotransfected with SSTR5 and dopamine D2 receptor are exposed to an appropriate agonist, a heterdimer is formed, composed of the two receptor types (24). Several receptors bind to related but different receptors as well as to each other (25). Dimerization of somatostatin receptor subtypes is induced by agonist binding and is accompanied by modified functionality (26). SSTR2 or SSTR5 agonists used individually had no effect on PDGF-stimulated Ras activity in human neuroblastoma cells; however, combined stimulation of SSTR2 and SSTR5 resulted in inhibitory effects (23). A biselective SSTR2 and 5 agonist, BIM-23244, has been demonstrated to have enhanced efficacy in suppressing GH from octreotide-resistant human GH-secreting adenomas (8). These reports of functional interaction between the SSTR2 and -5 receptor subtypes suggest the possibility of SSTR heterodimerization. Using double immunostaining or in situ hybridization, SSTR2 and SSTR5 were shown to be widely distributed in the rat pituitary and colocalized GH-secreting cells (4, 20). These morphologic observations suggest that SSTR2 and SSTR5 subtypes are appropriately located to facilitate physical interaction and possible heterodimerization.

The results of the present study demonstrate that either SSTR2 or SSTR5 may independently suppress GH secretion from the human fetal pituitary. Activation of both SSTR2 and SSTR5 induces a functional, synergistic association of the receptor subtypes that results in enhanced suppression of GH secretion. The ability of an SSTR2 selective antagonist to inhibit the GH-suppressing action when both SSTR2 and SSTR5 are activated may indicate disruption of the functional interaction between the SSTR2 and SSTR5 subtypes. This hypothesis may be further examined in the future by use of an SSTR5-specific antagonist.

SSTRs are distributed in a variety of human neuroendocrine tumors, and SRIF analogs are frequently used for diagnosis and treatment of these tumors, resulting in suppressed hormone secretion and modest tumor shrinkage (2, 3, 4, 27, 28, 29, 30). Because of heterogeneous SSTR expression and the distinct functions of SSTR subtypes in different cells, SSTR-specific SRIF analogs may be of benefit in treating patients with specific SSTR subtype-positive tumors (31, 32). SSTR subtype-specific agonists and antagonists are useful tools to investigate the physiologic functions of endogenous SRIF and its receptors and also elucidate novel concepts and with therapeutic utility.

	Acknowledgments

 
We thank Mrs. Grace Labrado for her help in preparing this manuscript.

	Footnotes

 
This work was supported by grants from Biomeasure Inc., the Doris Factor Molecular Endocrinology Laboratory, and the Annenberg Foundation.

Abbreviations: CHO, Chinese hamster ovary; Ki, affinity constant; PRL, prolactin; SRIF, somatostatin; SSTR, SRIF receptor.

Received February 21, 2003.

Accepted May 20, 2003.

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