Somatostatin Dramatically Stimulates Growth Hormone Release from Primate Somatotrophs Acting at Low Doses Via Somatostatin Receptor 5 and Cyclic AMP

Córdoba-Chacón, José; Gahete, Manuel D.; Culler, Michael D.; Castaño, Justo P.; Kineman, Rhonda D; Luque, Raúl M.

doi:10.1111/j.1365-2826.2011.02261.x

Cited by 44 publications

(39 citation statements)

References 58 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In particular, SST and CORT are two primary inhibitors of GH secretion by acting through their canonical receptors (sst1-5). Specifically, we have recently published that both SST and/or CORT can inhibit basal GH secretion (7,8) and block GHRHand ghrelin-induced GH release (18,19). Accordingly, SST-KO or CORT-KO mice display markedly elevated plasma GH levels (8,10).…”

Section: Discussionmentioning

confidence: 97%

Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels

et al. 2015

Self Cite

View full text Add to dashboard Cite

Somatostatin (SST) and cortistatin (CORT) are two highly related neuropeptides involved in the regulation of various endocrine secretions. In particular, SST and CORT are two primary negative regulators of GH secretion. Consequently, single SST or CORT knockout mice exhibit elevated GH levels; however, this does not lead to increased IGF-1 levels or somatic growth. This apparent lack of correspondence has been suggested to result from compensatory mechanisms between both peptides. To test this hypothesis, in this study we explored, for the first time, the consequences of simultaneously deleting endogenous SST and CORT by generating a double SST/CORT knockout mouse model and exploring its endocrine and metabolic phenotype. Our results demonstrate that simultaneous deletion of SST and CORT induced a drastic elevation of endogenous GH levels, which, surprisingly, did not lead to changes in growth rate or IGF-1 levels, suggesting the existence of additional factors/systems that, in the absence of endogenous SST and CORT, could counteract GH actions. Notably, elevation in circulating GH levels were not accompanied by changes in pituitary GH expression or by alterations in the expression of its main regulators (GHRH and ghrelin) or their receptors (GHRH receptor, GHS receptor, or SST/CORT receptors) at the hypothalamic or pituitary level. However, although double-SST/CORT knockout male mice exhibited normal glucose and insulin levels, they had improved insulin sensitivity compared with the control mice. Therefore, these results suggest the existence of an intricate interplay among the known (SST/CORT), and likely unknown, inhibitory components of the GH/IGF-1 axis to regulate somatic growth and glucose/insulin homeostasis.

show abstract

Section: Discussionmentioning

confidence: 97%

Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this context, previous studies from our group showing that sst5-or sst5-related mechanisms may also be involved in mediating unique actions of SST and CORT in these species prompted us to investigate in more detail pig sst5 (5,8,16). Accordingly, in the present study, we describe for the first time the cloning, isolation, and characterization of the porcine sst5 gene (psst5), which, upon processing of two cryptic introns, originates three sst5 receptors, the wild-type receptor with seven TMDs, and two truncated variants with six and four * M. Durán-Prado and M. D. Gahete contributed equally to this work.…”

mentioning

confidence: 99%

Truncated variants of pig somatostatin receptor subtype 5 (sst5) act as dominant-negative modulators for sst2-mediated signaling

Durán-Prado

Gahete

Delgado-Niebla

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Navarro F, Malagon MM, Luque RM, Castaño JP. Truncated variants of pig somatostatin receptor subtype 5 (sst5) act as dominantnegative modulators for sst2-mediated signaling. Am J Physiol Endocrinol Metab 303: E1325-E1334, 2012. First published October 2, 2012; doi:10.1152/ajpendo.00445.2012.-Somatostatin (SST) and its related peptide cortistatin (CORT) exert their multiple actions through binding to the SST receptor (sst) family, generally considered to comprise five G protein-coupled receptors with seven transmembrane domains (TMD), named sst1-sst5, plus a splice sst2B variant. However, we recently discovered that human and rodent sst5 gene expression also generates, through noncanonical alternative splicing, novel truncated albeit functional sst5 variants with less than seven TMD. Here, we cloned and characterized for the first time the porcine wild-type sst5 (psst5, full-length) and identified two novel truncated psst5 variants with six and three TMD, thus termed psst5TMD6 and psst5TMD3, respectively. In line with that observed in human and rodent truncated sst5 variants, psst5TMD6 and psst5TMD3 are functional (e.g., activate calcium signaling), selectively respond to SST and CORT, respectively, and exhibit specific tissue expression profiles that differ from full-length psst5 and often overlaps with psst2 expression. Moreover, fluorescence resonance energy transfer analysis shows that psst5 truncated variants physically interact with psst2, thereby altering their localization at the plasma membrane and specifically disrupting the cellular response to SST and/or CORT. These results represent the first characterization of a key porcine SST receptor, psst5, and, together with our previous results, provide strong evidence that alternative splicing-derived, truncated sst5 variants with distinct functional capacities exist in the mammalian lineage, where they can act as dominant-negative receptors, by interacting directly with long, seven TMD variants, potentially contributing to modulate normal and pathological SST and CORT signaling. somatostatin; cortistatin; somatostatin receptor; truncated receptor; dominant-negative receptor SOMATOSTATIN (SST) is a neuropeptide that exerts its multiple actions, including inhibition of neuroendocrine secretions, neurotransmission, and regulation of gastrointestinal functions, through a family of receptors (sst) belonging to the superfamily of G protein-coupled receptors (GPCR) with seven transmembrane domains (TMDs) (24,27). In mammals, the sst family comprises five distinct receptors (sst1-5) encoded by different, nonallelic, and intronless genes (24,27,28,38) and, in some species, an alternatively COOH-terminal spliced isoform of the sst2, the sst2B, originated by processing of a cryptic intron located in the 3=-untranslated region (UTR) (28, 36). These receptors also mediate the effects of cortistatin (CORT), a peptide that shows a remarkable sequential and structural homology with SST (10). In fact, SST and CORT share many actions, especially their ability to regulate the...

show abstract

“…Furthermore, from a more general perspective, these results reinforce the contention that there are specific subpopulations of somatotropes with a quantitatively and qualitatively distinct set of sst receptors that through their interactions would finely define the responsiveness of these cells to SST. Because a dual stimulatory-inhibitory response of somatotropes to high/low doses of SST and cortistatin (another endogenous ligand for ssts) has been observed and characterized in a nonhuman primate specie, baboon (8,9), these results might be relevant for humans from a physiological point of view. In summary, we have cloned and characterized, for the first time, psst1 and have shown its widespread tissue distribution, specific functional properties, and particular ability to interact with other pssts and with itself, thus providing a suitable model and additional tools to explore sst1 and psst (patho)physiology.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, we have previously demonstrated that high doses of SST inhibit ghrelin-or GH-releasing hormone (GHRH)-stimulated GH secretion, whereas, surprisingly, low doses of SST can stimulate basal GH release from primary pituitary cell cultures of pigs and primates, being sst1 and sst2 mainly involved in the inhibitory response to SST, whereas sst5 is the major determinant of the atypical stimulatory action of this peptide on pituitary somatotropes (8,9,28,29,39). Moreover, our data indicate that the pituitary response to SST is markedly different depending on the somatotrope subpopulation studied [low-density (LD) vs. high-density (HD) subpopulations] and that this different response is, likely, due to the unique distribution and abundance of the ssts in both somatotrope subpopulations (28).…”

mentioning

confidence: 99%

“…In addition, sst1 is one of the ssts that has been involved in the paradoxical dual stimulatory-inhibitory action of SST on growth hormone (GH) secretion observed in various mammalian species such as pigs and primates, which is dependent on the dose and the pituitary cell subpopulation tested (8,9,28,29,39). Specifically, we have previously demonstrated that high doses of SST inhibit ghrelin-or GH-releasing hormone (GHRH)-stimulated GH secretion, whereas, surprisingly, low doses of SST can stimulate basal GH release from primary pituitary cell cultures of pigs and primates, being sst1 and sst2 mainly involved in the inhibitory response to SST, whereas sst5 is the major determinant of the atypical stimulatory action of this peptide on pituitary somatotropes (8,9,28,29,39).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Porcine sst1 can physically interact with other somatostatin receptors, and its expression is regulated by metabolic/inflammatory sensors

Gahete

Durán-Prado

Delgado-Niebla

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

The majority of the biological actions attributed to somatostatin (SST) are thought to be mediated by SST receptor 2 (sst2), the most ubiquitous sst, and, to a lesser extent, by sst5. However, a growing body of evidence suggests a relevant role of sst1 in mediating SST actions in (patho)physiological situations (i.e., endometriosis, type 2 diabetes). Moreover, sst1 together with sst2 and sst5 is involved in the well-known actions of SST on pituitary somatotropes in pig and primates. Here, we cloned the porcine sst1 (psst1) and performed a structural and functional characterization using both primary and heterologous models. The psst1 sequence presents the majority of signature motifs shared among G proteincoupled receptors and, specifically, among ssts and exhibits a high homology with other mammalian sst1, with only minor differences in the amino-terminal domain, reinforcing the idea of an early evolutive divergence between mammalian and nonmammalian sst1s. psst1 is functional in terms of decreasing cAMP levels in response to SST when transfected in heterologous models. The psst1 receptor is expressed in several tissues, and analyses of gene cis elements predict regulation by multiple transcription factors and metabolic stimuli. Finally, psst1 is coexpressed with other sst subtypes in various tissues, and in vitro data demonstrate that psst1 can interact with itself forming homodimers and with other ssts forming heterodimers. These data highlight the functional importance of sst1 on the SST-mediated effects and its functional interaction with different ssts, which point out the necessity of exploring the consequences of such interactions. somatostatin receptor 1, promoter regulation; expression profile; heterodimerization; fluorescence resonance energy transfer; adenosine 3=,5=-cyclic monophosphate SOMATOSTATIN (SST) is a peptide hormone mainly produced by neuroendocrine cells (18,50). It was first isolated from the ovine hypothalamus (6), and soon thereafter isolated and sequenced in porcine hypothalami (45). SST acts as an endogenous inhibitory regulator of various cellular functions, including hormone secretion, motility, and proliferation (5,11,26,32,36,40). SST has two active forms (14 and 28 amino acids) with comparable subnanomolar affinity for a family of G protein-coupled receptors (GPCRs) widely distributed in the brain and periphery and named SST receptors (ssts) (34, 36). To date, five separate sst genes have been described (sst1-sst5), encoding six to nine different isoforms, depending on the species (10,14,16,36). Although more than one sst subtype can be simultaneously expressed in certain cell types, the expression pattern and levels depend on the tissue, the age, and the physiological status (11,29,36).The majority of biological actions associated with SST are thought to be mediated by sst2, the most ubiquitous sst, and, to a lesser extent, by sst5. However, a growing body of evidence suggests a relevant role of sst1 in mediating SST actions in physiological and pathophysiological situations. I...

show abstract

Somatostatin Dramatically Stimulates Growth Hormone Release from Primate Somatotrophs Acting at Low Doses Via Somatostatin Receptor 5 and Cyclic AMP

Cited by 44 publications

References 58 publications

Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels

Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels

Truncated variants of pig somatostatin receptor subtype 5 (sst5) act as dominant-negative modulators for sst2-mediated signaling

Porcine sst1 can physically interact with other somatostatin receptors, and its expression is regulated by metabolic/inflammatory sensors

Contact Info

Product

Resources

About