Signal transduction of the gonadotropin releasing hormone (GnRH) receptor: Cross-talk of calcium, protein kinase C (PKC), and arachidonic acid

Naor, Zvi; Shacham, Sharon; Harris, Dagan; Seger, Rony; Reiss, Nachum

doi:10.1007/bf02071315

Cited by 46 publications

(26 citation statements)

References 132 publications

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“…In addition, it has been recently reported that the abolition of Ca 2+ signals is not a primary mechanism through which SRIF lowers GH release (Yunker and Chang 2001). Since the PLA 2 /AA pathway seems to be involved in secretory events in different experimental models (Naor et al 1995;Mizuno et al 2000;Ehses et al 2001), it is tempting to speculate that the inhibition of AA release may be responsible for the SRIF control of GH secretion in GC cells.…”

Section: Involvement Of Camp-dependent Pathwaysmentioning

confidence: 96%

Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release

Cervia

Fiorini

Pavan

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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The somatotropin release-inhibiting factor somatostatin-14 (SRIF) is known to activate distinct receptor subtypes (sst1-5). In rat pituitary tumor cells (GC cells), sst2 but not sst1 receptors mediate the SRIF-induced inhibition of intracellular concentration of Ca2+ ([Ca2+]i) and are negatively coupled to cAMP-dependent pathways. In the present study, transduction mechanisms coupling distinct SRIF receptors to their specific functional role were investigated with the use of both SRIF agonists with well-known affinity at individual SRIF receptors and the sst2 receptor antagonist L-Tyr(8) isomer of Cyanamid 154806 (CYN-154806). Our results demonstrate that sst1 and sst2 receptors are coupled to distinct signaling pathways in GC cells. In particular, sst2 receptors are negatively coupled to the cAMP-dependent pathway and this pathway is partially responsible for the sst2 receptor-mediated inhibition of [Ca2+]i. In addition, sst1 and sst2 receptors are both coupled to a decrease of arachidonic acid (AA) release with an efficacy similar to that of SRIF, suggesting that SRIF reduces AA release through either a partial activation of both receptors or the activation of one at a time. This finding is important given the well-accepted role for phospholipase A2 (PLA2) as a positive signaling component in transduction pathways of SRIF receptors. sst1 and sst2 receptor negative coupling to PLA2/AA pathways does not seem to be implicated in the SRIF-induced inhibition of [Ca2+]i. The possible role for the SRIF-mediated inhibition of AA release in GC cell function remains to be elucidated.

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Section: Involvement Of Camp-dependent Pathwaysmentioning

confidence: 96%

Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release

Cervia

Fiorini

Pavan

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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“…In GC cells, sst 2 receptors that are coupled to [Ca 2+ ] i control, modulate cAMP pathways, whereas sst 1 receptors are coupled to phospholipase A 2 pathways independently of [Ca 2+ ] i control [15]. Since the phospholipase A 2 pathway is involved in secretory events in different experimental models [37, 38, 39], it is tempting to speculate that the inhibition of this pathway may be also responsible for the sst 1 control of GH secretion in GC cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Control of Growth Hormone Secretion by Somatostatin in Rat Pituitary GC Cells: sst<sub>2</sub> but Not sst<sub>1</sub> Receptors Are Coupled to Inhibition of Single-Cell Intracellular Free Calcium Concentrations

Cervia

Petrucci²,

Bluet-Pajot³

et al. 2002

Neuroendocrinology

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Rat pituitary tumor cells (GC cells) exhibit spontaneous oscillations of intracellular free calcium concentration ([Ca²⁺]_i) that allow continuous release of growth hormone (GH). Of the somatostatin (SRIH) receptor subtypes (sst receptors) mediating SRIH action, sst₁ and sst₂ receptors are highly expressed by GC cell membranes. In the present study, the effects of sst₁ or sst₂ receptor activation on single-cell [Ca²⁺]_i were investigated in GC cells by confocal fluorescence microscopy. In addition, the effects of sst₁ or sst₂ receptor activation on GH secretion were also studied. Our results demonstrate that SRIH decreases [Ca²⁺]_i baseline and almost completely blocks Ca²⁺ transients through activation of sst₂ but not of sst₁ receptors. In contrast, SRIH effectively inhibits GH secretion through activation of both sst₁ and sst₂ receptors. Blocking Ca²⁺ transients is less efficient than SRIH to inhibit GH release. The cyclic octapeptide, CYN-154806, antagonizes sst₂ receptors at [Ca²⁺]_i since it abolishes the sst₂ receptor-mediated inhibition of [Ca²⁺]_i without affecting single-cell Ca²⁺ signals. On the other hand, CYN-154806 alone potently inhibits GH secretion through the involvement of pertussis toxin-sensitive G proteins. In conclusion, the present results demonstrate that SRIH inhibition of GH release in GC cells involves mechanisms either dependent or independent on SRIH modulation of [Ca²⁺]_i. The implications of CYN-154806 inhibition of GH secretion are discussed.

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“…G q/11 -coupled receptors are also involved in the signal transduction of several hypothalamic peptide hormone receptors, such as the receptors for thyrotropin-releasing hormone (39), gonadotropin-releasing hormone (13), and prolactin-releasing hormones (3). There is an increasing amount of evidence that the release of hypothalamic hormones themselves is also controlled by G q/11 -coupled receptors.…”

mentioning

confidence: 99%

Loss of G_q/11 Family G Proteins in the Nervous System Causes Pituitary Somatotroph Hypoplasia and Dwarfism in Mice

Wettschureck

Moers

Wallenwein

et al. 2005

Molecular and Cellular Biology

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Heterotrimeric G proteins of the G q/11 family transduce signals from a variety of neurotransmitter and hormone receptors and have therefore been implicated in various functions of the nervous system. Using the Cre/loxP system, we generated mice which lack the genes coding for the ␣ subunits of the two main members of the G q/11 family, gnaq and gna11, selectively in neuronal and glial precursor cells. Mice with defective gnaq and gna11 genes were morphologically normal, but they died shortly after birth. Mice carrying a single gna11 allele survived the early postnatal period but died within 3 to 6 weeks as anorectic dwarfs. In these mice, postnatal proliferation of pituitary somatotroph cells was strongly impaired, and plasma growth hormone (GH) levels were reduced to 15%. Hypothalamic levels of GH-releasing hormone (GHRH), an important stimulator of somatotroph proliferation, were strongly decreased, and exogenous administration of GHRH restored normal proliferation. The hypothalamic effects of ghrelin, a regulator of GHRH production and food intake, were reduced in these mice, suggesting that an impairment of ghrelin receptor signaling might contribute to GHRH deficiency and abnormal eating behavior. Taken together, our findings show that G q/11 signaling is required for normal hypothalamic function and that impairment of this signaling pathway causes somatotroph hypoplasia, dwarfism, and anorexia.The G q/11 family of heterotrimeric G proteins mediates the cellular effects of numerous neurotransmitter receptors, e.g., the metabotropic glutamate receptor subtypes 1 and 5, the M 1 muscarinic-acetylcholine receptor, the 5-HT 2 serotonin receptors, or the ␣ 1 adrenergic receptor. G q/11 -coupled receptors are also involved in the signal transduction of several hypothalamic peptide hormone receptors, such as the receptors for thyrotropin-releasing hormone (39), gonadotropin-releasing hormone (13), and prolactin-releasing hormones (3). There is an increasing amount of evidence that the release of hypothalamic hormones themselves is also controlled by G q/11 -coupled receptors. Kisspeptins, for example, have been suggested to control the release of gonadotropin-releasing hormone via the G q/11 -coupled receptor GPR54 (14,20), and the gastrointestinal peptide hormone ghrelin regulates the production of growth hormone-releasing hormone (GHRH) via the hypothalamic growth hormone secretagogue receptor (GHS-R) (12,22). G q/11 family G proteins mediate the activation of ␤ isoforms of phospholipase C, resulting in the activation of protein kinase C and intracellular calcium mobilization (2). The G q/11 family consists of four members, two of which, G q and G 11 , are expressed almost ubiquitously in the central nervous system (26). Genetic inactivation of the gnaq gene, which codes for the ␣ subunit of G q (G␣ q ), leads to a defect in primary hemostasis (16) and cerebellar ataxia (15). In contrast, mice homozygous for a null allele of the gene coding for G␣ 11 , gna11, did not show any phenotypic abnormalities (17). These...

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Signal transduction of the gonadotropin releasing hormone (GnRH) receptor: Cross-talk of calcium, protein kinase C (PKC), and arachidonic acid

Cited by 46 publications

References 132 publications

Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release

Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release

Inhibitory Control of Growth Hormone Secretion by Somatostatin in Rat Pituitary GC Cells: sst<sub>2</sub> but Not sst<sub>1</sub> Receptors Are Coupled to Inhibition of Single-Cell Intracellular Free Calcium Concentrations

Loss of G_q/11 Family G Proteins in the Nervous System Causes Pituitary Somatotroph Hypoplasia and Dwarfism in Mice

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Signal transduction of the gonadotropin releasing hormone (GnRH) receptor: Cross-talk of calcium, protein kinase C (PKC), and arachidonic acid

Cited by 46 publications

References 132 publications

Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release

Somatostatin (SRIF) modulates distinct signaling pathways in rat pituitary tumor cells; negative coupling of SRIF receptor subtypes 1 and 2 to arachidonic acid release

Inhibitory Control of Growth Hormone Secretion by Somatostatin in Rat Pituitary GC Cells: sst<sub>2</sub> but Not sst<sub>1</sub> Receptors Are Coupled to Inhibition of Single-Cell Intracellular Free Calcium Concentrations

Loss of Gq/11 Family G Proteins in the Nervous System Causes Pituitary Somatotroph Hypoplasia and Dwarfism in Mice

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Loss of G_q/11 Family G Proteins in the Nervous System Causes Pituitary Somatotroph Hypoplasia and Dwarfism in Mice