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Role of thyrotropin-releasing hormone in prolactin-producing cell models
YNPEP-01647; No of Pages 5 Neuropeptides xxx (2015) xxx–xxx
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Role of thyrotropin-releasing hormone in prolactin-producing cell models Haruhiko Kanasaki ⁎, Aki Oride, Tselmeg Mijiddorj, Satoru Kyo Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan
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Article history: Received 8 July 2015 Received in revised form 3 August 2015 Accepted 3 August 2015 Available online xxxx Keywords: TRH Prolactin GH3 PACAP
a b s t r a c t Thyrotropin-releasing hormone (TRH) is a hypothalamic hypophysiotropic neuropeptide that was named for its ability to stimulate the release of thyroid-stimulating hormone in mammals. It later became apparent that it exerts a number of species-dependent hypophysiotropic activities that regulate other pituitary hormones. TRH also regulates the synthesis and release of prolactin, although whether it is a physiological regulator of prolactin that remains unclear. Occupation of the Gq protein-coupled TRH receptor in the prolactin-producing lactotroph increases the turnover of inositol, which in turn activates the protein kinase C pathway and the release of Ca2+ from storage sites. TRH-induced signaling events also include the activation of extracellular signal-regulated kinase (ERK) and induction of MAP kinase phosphatase, an inactivator of activated ERK. TRH stimulates prolactin synthesis through the activation of ERK, whereas prolactin release occurs via elevation of intracellular Ca2+. We have been investigating the role of TRH in a pituitary prolactin-producing cell model. Rat pituitary somatolactotroph GH3 cells, which produce and release both prolactin and growth hormone (GH), are widely used as a model for the study of prolactin- and GH-secreting cells. In this review, we describe the general action of TRH as a hypophysiotropic factor in vertebrates and focus on the role of TRH in prolactin synthesis using GH3 cells. © 2015 Elsevier Ltd. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Effect of TRH on pituitary cells . . . . . . . . . . . . . . . . . . . . . . 3. TRH as a prolactin-releasing factor . . . . . . . . . . . . . . . . . . . . 4. Rat pituitary somatolactotroph GH3 cell line. . . . . . . . . . . . . . . . 5. Intracellular signaling evoked by TRH in GH3 cells . . . . . . . . . . . . . 6. TRH signaling and prolactin synthesis/secretion . . . . . . . . . . . . . . 7. Mode of TRH delivery and the effect on prolactin expression . . . . . . . . 8. Interaction of TRH and adenylate cyclase-activating polypeptide in lactotrophs 9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Thyrotropin-releasing hormone (TRH) was initially isolated from ovine and porcine hypothalamic extracts due to its ability to stimulate the release of thyroid-stimulating hormone (TSH) from rat pituitary cells (Nair et al., 1970; Burgus et al., 1970). The TRH sequence (pGluHis-Pro-NH2) has been fully conserved from fish to mammals, but this peptide is known to exert diverse, species-specific effects on the ⁎ Corresponding author at: Shimane University, School of Medicine, Dept. of Obstetrics and Gynecology, 89-1 Enya Cho, Izumo City 693-8501, Shimane Prefecture, Japan. E-mail address: [email protected] (H. Kanasaki).
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pituitary gland. TRH is widely expressed in various brain regions and the spinal cord (Poulat et al., 1992; Merchenthaler et al., 1988), as well as in a number of peripheral organs, including the pituitary (Le Dafniet et al., 1990), thyroid (Iversen et al., 1984), placenta (Shambaugh et al., 1979), pancreas (Leduque et al., 1989) and testis (Montagne et al., 1996). 2. Effect of TRH on pituitary cells Although TRH was originally named as a TSH-releasing hormone, there is now considerable evidence that TRH is involved in speciesspecific hypophysiotropic functions. The levels of TRH in several species
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Please cite this article as: Kanasaki, H., et al., Role of thyrotropin-releasing hormone in prolactin-producing cell models, Neuropeptides (2015), http://dx.doi.org/10.1016/j.npep.2015.08.001
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H. Kanasaki et al. / Neuropeptides xxx (2015) xxx–xxx
of fish, such as carp, tilapia and African lungfish, are not capable of stimulating TSH (Kagabu et al., 1998; Melamed et al., 1995; Gorbman and Hyder, 1973). In other types of fish, TRH exerts a modest effect on TSH stimulation, and corticotropin-releasing hormone (CRH) seems to play the role of a TSH-releasing factor, at least in coho salmon (Larsen et al., 1998). Indeed, in amphibians, CRH appears to be the major TSHstimulating factor (Okada et al., 2009). TRH is known to stimulate the secretion of growth hormone (GH) in carp (Kagabu et al., 1998) and is a potent stimulator of α-melanocyte-stimulating hormone in teleost fish (Tran et al., 1989). TRH is also a potent stimulator of prolactin secretion in amphibians (Castano et al., 1993) and is the major prolactinreleasing factor in the hypothalamus of the bullfrog (Nakajima et al., 1993). In the pituitary in mammals, TRH stimulates not only TSH, but also prolactin and GH (Szabo et al., 1984; Tashjian et al., 1971). 3. TRH as a prolactin-releasing factor Shortly after its initial identification as a TSH-releasing factor, TRH was shown to cause the rapid release of prolactin from rat anterior pituitary cells (Tashjian et al., 1971). However, it is not clear whether TRH is a physiological regulator of prolactin. Indeed, a number of different experimental approaches have failed to clarify the physiological role of TRH. In humans, the same concentrations of TRH that release TSH also release prolactin (Noel et al., 1974). In rats, the neutralization of endogenous TRH with TRH antisera suppresses the basal secretion of prolactin (Koch et al., 1977), and suckling causes an increase in hypothalamic and portal TRH levels along with a decrease in dopamine levels (de Greef et al., 1981). In human hypothyroidism, basal levels of TSH and prolactin, as well as their response to TRH, are increased (Snyder et al., 1973). On the contrary, immunoneutralization of TRH did not affect the magnitude of prolactin release in proestrus rats (Horn et al., 1985). TRH knockout mice displayed hypothyroidism with elevated TSH but had normal prolactin levels (Yamada et al., 1997). However, observations of TSH levels during lactation and the evaluation of prolactin levels in various thyroid states suggest that TRH is a physiological prolactin-releasing factor, albeit not the primary factor or one of major importance. 4. Rat pituitary somatolactotroph GH3 cell line Pituitary somatotrophs and lactotrophs are both acidophilic cells and are believed to derive from the same origin. In the anterior pituitary gland of normal adult rats, acidophilic cells are almost equally divided into somatotrophs, lactotrophs and somatolactotrophs (Frawley et al., 1985). Somatolactotrophs, however, appear earlier than somatotrophs and lactotrophs during neonatal development in rats, and the proportion of lactotrophs has been reported to be only 1.7% of all anterior pituitary cells (Hoeffler et al., 1985). These observations suggest the possibility that prolactin-secreting cells arise from GH-secreting cells. GH3 cells, established from rat pituitary adenoma, can synthesize and secrete both prolactin and GH, and exist as either somatotrophs or somatolactotrophs (Boockfor and Schwarz, 1988). Thus, GH3 cells are widely used as a model to study the functions of normal pituitary acidophilic cells. 5. Intracellular signaling evoked by TRH in GH3 cells It is known that TRH stimulates production of inositol phospholipid by activating the Gq protein-coupled TRH receptor in lactotrophs. This in turn stimulates the protein kinase C pathway (PKC) and Ca2+ release from Ca2+ storage sites (Gershengorn, 1986). TRH-induced signaling activates the extracellular signal-regulated kinase (ERK) via PKCdependent and PKC-independent pathways—the former pathway activates MEK kinase (MEKK) via PKA and the latter induces Rasdependent MEKK activation via tyrosine phosphorylation of Shc proteins. MEKK activates MEK by phosphorylation and ultimately ERK is
activated by MEK (Winitz et al., 1993; Ohmichi et al., 1994). TRHinduced ERK activation is inactivated via dephosphorylation by dual specificity protein phosphatases, MAP kinase phosphatases (MKPs) (Oride et al., 2009). On the other hand, the elevation of intracellular Ca2 + levels from Ca2 + storage sites, via the mobilization of inositol phospholipid or the influx of extracellular Ca2 + through calcium channels, activates Ca2 +-dependent protein kinases such as Ca2 +/ calmodulin-dependent protein kinase II (Jefferson et al., 1991; Cui et al., 1994). 6. TRH signaling and prolactin synthesis/secretion The TRH-induced release and synthesis of prolactin are regulated by different signaling cascades. The TRH-induced activation of ERK is strongly involved in prolactin gene expression, as shown by the expression of TRH-induced prolactin mRNA being completely inhibited in the presence of a MEK (an activator of ERK) inhibitor (Kanasaki et al., 1999, 2002). In addition, overexpression of the constitutively active form of MEKK increases the expression of endogenous prolactin mRNA (Kanasaki et al., 2002). These observations are explained by the fact that the prolactin promoter contains binding sites such as Ets-1 and GFH-1/Pit-1, both of which synergistically enhance the synthesis of prolactin in a Ras/Raf response element within the prolactin promoter that is related to ERK signaling pathways (Bradford et al., 1995). However, the release of TRH-stimulated prolactin does not occur via ERK activation. The MEK inhibitor did not inhibit the release of TRH-induced prolactin, but it did inhibit it in the presence of the inhibitor for Ca2 +/ calmodulin-dependent protein kinase II or myosin light chain kinase, both of which are dependent upon Ca2+ for activation (Kanasaki et al., 1999, 2002). These observations clearly demonstrate that hormone release and synthesis are regulated differently by TRH stimulation. In GH3 cells, both prolactin and GH are regulated by TRH stimulation; GH synthesis is reduced by TRH, whereas prolactin synthesis is stimulated (Kanasaki et al., 2002). Previous studies have demonstrated that treating GH3 cells with TRH results in an increased number of prolactin-producing cells and a decreased number of GH-secreting cells (Boockfor et al., 1985; Schonbrunn et al., 1980). Epidermal growth factor (EGF) has an effect similar to that of TRH as it increases prolactin and decreases GH levels in GH4Cl cells, a subclone of GH3 cells (Schonbrunn et al., 1980). TRH-induced ERK activation is strongly involved in this phenomenon as the inhibition of ERK does not increase prolactin synthesis but increases GH synthesis. In addition, overexpression of the constitutively active form of MEKK decreases GH synthesis (Kanasaki et al., 2002). If an increasing population of prolactin-producing cell was in the more differentiated stage among somatolactotrophs, it is possible that TRH could act as a differentiation-promoting factor, leading to a decrease in the proportion of somatotrophs and an increase in the proportion of lactotrophs. The proposed mechanisms of TRH action in hormone synthesis and release in GH3 cells is shown in Fig. 1. 7. Mode of TRH delivery and the effect on prolactin expression It is well known that hypothalamic gonadotropin-releasing hormone (GnRH) is delivered into portal circulation in a pulsatile manner and its pulse frequency determines predominant output of pituitary gonadotropins, namely luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Crowley et al., 1985). The release of GnRH needs to be in a pulsatile manner, and not continuous, to maintain the secretion of gonadotropins (Knobil, 1980). In addition, a more rapid pulse frequency of GnRH predominantly increases the secretion of LH, whereas a slower pulse frequency of GnRH decreases LH secretion and increases FSH release (Wildt et al., 1981). As for TRH, its secretion was found to be episodic and irregular in the venous blood of the pituitary in mares (Alexander et al., 2004), whereas in humans TRH is released in a pulsatile manner with regard to frequency and amplitude (Adriaanse et al.,
Please cite this article as: Kanasaki, H., et al., Role of thyrotropin-releasing hormone in prolactin-producing cell models, Neuropeptides (2015), http://dx.doi.org/10.1016/j.npep.2015.08.001
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Fig. 1. Schematic summary of the role of TRH in somatolactotroph GH3 cells. TRH binds to the Gq protein-coupled TRH receptor and induces Raf (MEKK) activation via PKC-dependent and -independent pathways. ERK is activated through MEKK/MEK activation and increases prolactin gene expression. ERK activation is also involved in growth hormone (GH) inhibition as well as cell growth inhibition, whereas intracellular Ca2+ from intracellular Ca2+ storage sites or extracellular sites activates Ca2+-dependent protein kinases, such as calcium/calmodulin-dependent kinase II (CaML II) or myosin light chain kinase (MLCK), that accelerate both prolactin and GH release.
1992). These observations suggest that circulating TRH levels are not continuously maintained, but TRH is released as a hormonal pulse. We previously examined how pulsatile TRH affects somatolactotroph GH3 cells and the transcriptional activity of prolactin promoters. Experiments were performed using a perifusion system to perifuse TRH in a pulsatile manner, and pulsatile TRH stimulation at 30-min intervals increased prolactin promoter activity in a similar manner to that following continuous TRH stimulation. In addition, we found that a higher TRH pulse frequency (1 pulse/30 min) was more effective in obtaining maximal activity compared with a low TRH pulse frequency (1 pulse/120 min) (Oride et al., 2008). These findings suggest that an increased exposure of cells to TRH results in an increased production of prolactin. Although ERK activation induced by TRH is strongly involved in prolactin synthesis as described above, the strength or duration of ERK activation is not correlated with prolactin promoter activity in experiments using a static culture. In addition, it seems that transient occupation of the TRH receptor is important to initiate the stimulation of prolactin promoter activity in static conditions as the prolactin promoter activity was similar when cells were exposed to TRH for 10 min or for 6 h (Oride et al., 2008). 8. Interaction of TRH and adenylate cyclase-activating polypeptide in lactotrophs Pituitary adenylate cyclase-activating polypeptide (PACAP) is a hypothalamic peptide that affects lactotroph functionality. PACAP was
originally isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP in anterior pituitary cells (Miyata et al., 1989). Although PACAP was first reported to lack prolactin-releasing activity in cultured rat adenohypophyseal cells (Hart et al., 1992), later studies showed that prolactin release from rat pituitary cells can be slightly increased by treatment with PACAP (Arbogast and Voogt, 1994; Jarry et al., 1992). PACAP receptors are expressed in all cell types of rat adenohypophysis (Rawlings and Hezareh, 1996), and pituitary lactotrophs predominantly express the PACAP type I receptor (PAC1R) (Vertongen et al., 1995). We have previously shown that PACAP can stimulate prolactin gene expression in a lactotroph cell model, although the effect was limited compared with TRH stimulation. If cells adequately express PAC1R by overexpressing PAC1R, the response of prolactin promoters to PACAP was similar to the response to TRH. In addition, PACAP potentiates the effect of TRH on prolactin expression. Interestingly, overexpression of cellular PAC1R increases the basal levels of transcriptional activity of the prolactin promoter as well as the TRH-induced prolactin promoter activity (Mijiddorj et al., 2011), suggesting that both the TRH receptor and PAC1R cooperate with each other and produce more prolactin. Prolonged stimulation with TRH desensitizes its own TRH receptor and the response of prolactin promoters to TRH is eliminated. Furthermore, the response of prolactin promoters to PACAP is also eliminated by prolonged pretreatment with TRH. On the other hand, prolonged treatment with PACAP desensitizes PAC1R in the cells and the response of prolactin
Please cite this article as: Kanasaki, H., et al., Role of thyrotropin-releasing hormone in prolactin-producing cell models, Neuropeptides (2015), http://dx.doi.org/10.1016/j.npep.2015.08.001
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promoters to PACAP is eliminated, while the response of prolactin promoters to TRH is also eliminated by prolonged pretreatment with PACAP (Mijiddorj et al., 2013). These findings demonstrate that sustained stimulation with TRH and PACAP desensitizes their own and each other's receptors. Addition to the PACAP, hypothalamic peptide, cocaine- and amphetamine-regulated transcript (CART), has been reported to responsible for reduce TRH-induced prolactin release (Raptis et al., 2004). 9. Conclusions Since TRH was discovered 45 years ago, a substantial amount of information about its role has been accumulated. TRH is the principal hypothalamic factor that stimulates the release of TSH from the anterior pituitary in vertebrates and it is also known as a prolactin-releasing factor. In this review, we have summarized our understanding of the action of TRH in the pituitary lactotroph cell model involving GH3 cells. TRH exerts multiple species-dependent hypophysiotropic activities and a divergent effect on prolactin and GH in somatolactotroph cell models. TRH may interact with other neuropeptides, such as PACAP, at the receptor level. Novel information could be obtained by further studies involving TRH. References Adriaanse, R., et al., 1992. Circadian changes in pulsatile TSH release in primary hypothyroidism. Clin. Endocrinol. (Oxf) 37 (6), 504–510. Alexander, S.L., Irvine, C.H., Evans, M.J., 2004. Inter-relationships between the secretory dynamics of thyrotrophin-releasing hormone, thyrotrophin and prolactin in periovulatory mares: effect of hypothyroidism. J. Neuroendocrinol. 16 (11), 906–915. Arbogast, L.A., Voogt, J.L., 1994. Pituitary adenylate cyclase-activating polypeptide (PACAP) increases prolactin release and tuberoinfundibular dopaminergic neuronal activity. Brain Res. 655 (1–2), 17–24. Boockfor, F.R., Schwarz, L.K., 1988. Cultures of GH3 cells contain both single and dual hormone secretors. Endocrinology 122 (2), 762–764. Boockfor, F.R., Hoeffler, J.P., Frawley, L.S., 1985. Cultures of GH3 cells are functionally heterogeneous: thyrotropin-releasing hormone, estradiol and cortisol cause reciprocal shifts in the proportions of growth hormone and prolactin secretors. Endocrinology 117 (1), 418–420. Bradford, A.P., et al., 1995. Functional interaction of c-Ets-1 and GHF-1/Pit-1 mediates Ras activation of pituitary-specific gene expression: mapping of the essential c-Ets-1 domain. Mol. Cell. Biol. 15 (5), 2849–2857. Burgus, R., et al., 1970. Characterization of ovine hypothalamic hypophysiotropic TSHreleasing factor. Nature 226 (5243), 321–325. Castano, J.P., et al., 1993. Different exocytotic morphology in amphibian prolactin and growth hormone cells stimulated in vitro with TRH. Tissue Cell 25 (2), 165–172. Crowley Jr., W.F., et al., 1985. The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women. Recent Prog. Horm. Res. 41, 473–531. Cui, Z.J., Gorelick, F.S., Dannies, P.S., 1994. Calcium/calmodulin-dependent protein kinaseII activation in rat pituitary cells in the presence of thyrotropin-releasing hormone and dopamine. Endocrinology 134 (5), 2245–2250. de Greef, W.J., Plotsky, P.M., Neill, J.D., 1981. Dopamine levels in hypophysial stalk plasma and prolactin levels in peripheral plasma of the lactating rat: effects of a simulated suckling stimulus. Neuroendocrinology 32 (4), 229–233. Frawley, L.S., Boockfor, F.R., Hoeffler, J.P., 1985. Identification by plaque assays of a pituitary cell type that secretes both growth hormone and prolactin. Endocrinology 116 (2), 734–737. Gershengorn, M.C., 1986. Mechanism of thyrotropin releasing hormone stimulation of pituitary hormone secretion. Annu. Rev. Physiol. 48, 515–526. Gorbman, A., Hyder, M., 1973. Failure of mammalian TRH to stimulate thyroid function in the lungfish. Gen. Comp. Endocrinol. 20 (3), 588–589. Hart, G.R., Gowing, H., Burrin, J.M., 1992. Effects of a novel hypothalamic peptide, pituitary adenylate cyclase-activating polypeptide, on pituitary hormone release in rats. J. Endocrinol. 134 (1), 33–41. Hoeffler, J.P., Boockfor, F.R., Frawley, L.S., 1985. Ontogeny of prolactin cells in neonatal rats: initial prolactin secretors also release growth hormone. Endocrinology 117 (1), 187–195. Horn, A.M., Fraser, H.M., Fink, G., 1985. Effects of antiserum to thyrotrophin-releasing hormone on the concentrations of plasma prolactin, thyrotrophin and LH in the prooestrous rat. J. Endocrinol. 104 (2), 205–209. Iversen, E., Weeke, J., Laurberg, P., 1984. TRH immunoreactivity in the thyroid gland. Scand. J. Clin. Lab. Invest. 44 (8), 703–709. Jarry, H., et al., 1992. Contrasting effects of pituitary adenylate cyclase activating polypeptide (PACAP) on in vivo and in vitro prolactin and growth hormone release in male rats. Life Sci. 51 (11), 823–830. Jefferson, A.B., Travis, S.M., Schulman, H., 1991. Activation of multifunctional Ca2+/ calmodulin-dependent protein kinase in GH3 cells. J. Biol. Chem. 266 (3), 1484–1490.
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Role of thyrotropin-releasing hormone in prolactin-producing cell models Haruhiko Kanasaki ⁎, Aki Oride, Tselmeg Mijiddorj, Satoru Kyo Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan
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Article history: Received 8 July 2015 Received in revised form 3 August 2015 Accepted 3 August 2015 Available online xxxx Keywords: TRH Prolactin GH3 PACAP
a b s t r a c t Thyrotropin-releasing hormone (TRH) is a hypothalamic hypophysiotropic neuropeptide that was named for its ability to stimulate the release of thyroid-stimulating hormone in mammals. It later became apparent that it exerts a number of species-dependent hypophysiotropic activities that regulate other pituitary hormones. TRH also regulates the synthesis and release of prolactin, although whether it is a physiological regulator of prolactin that remains unclear. Occupation of the Gq protein-coupled TRH receptor in the prolactin-producing lactotroph increases the turnover of inositol, which in turn activates the protein kinase C pathway and the release of Ca2+ from storage sites. TRH-induced signaling events also include the activation of extracellular signal-regulated kinase (ERK) and induction of MAP kinase phosphatase, an inactivator of activated ERK. TRH stimulates prolactin synthesis through the activation of ERK, whereas prolactin release occurs via elevation of intracellular Ca2+. We have been investigating the role of TRH in a pituitary prolactin-producing cell model. Rat pituitary somatolactotroph GH3 cells, which produce and release both prolactin and growth hormone (GH), are widely used as a model for the study of prolactin- and GH-secreting cells. In this review, we describe the general action of TRH as a hypophysiotropic factor in vertebrates and focus on the role of TRH in prolactin synthesis using GH3 cells. © 2015 Elsevier Ltd. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Effect of TRH on pituitary cells . . . . . . . . . . . . . . . . . . . . . . 3. TRH as a prolactin-releasing factor . . . . . . . . . . . . . . . . . . . . 4. Rat pituitary somatolactotroph GH3 cell line. . . . . . . . . . . . . . . . 5. Intracellular signaling evoked by TRH in GH3 cells . . . . . . . . . . . . . 6. TRH signaling and prolactin synthesis/secretion . . . . . . . . . . . . . . 7. Mode of TRH delivery and the effect on prolactin expression . . . . . . . . 8. Interaction of TRH and adenylate cyclase-activating polypeptide in lactotrophs 9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Thyrotropin-releasing hormone (TRH) was initially isolated from ovine and porcine hypothalamic extracts due to its ability to stimulate the release of thyroid-stimulating hormone (TSH) from rat pituitary cells (Nair et al., 1970; Burgus et al., 1970). The TRH sequence (pGluHis-Pro-NH2) has been fully conserved from fish to mammals, but this peptide is known to exert diverse, species-specific effects on the ⁎ Corresponding author at: Shimane University, School of Medicine, Dept. of Obstetrics and Gynecology, 89-1 Enya Cho, Izumo City 693-8501, Shimane Prefecture, Japan. E-mail address: [email protected] (H. Kanasaki).
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pituitary gland. TRH is widely expressed in various brain regions and the spinal cord (Poulat et al., 1992; Merchenthaler et al., 1988), as well as in a number of peripheral organs, including the pituitary (Le Dafniet et al., 1990), thyroid (Iversen et al., 1984), placenta (Shambaugh et al., 1979), pancreas (Leduque et al., 1989) and testis (Montagne et al., 1996). 2. Effect of TRH on pituitary cells Although TRH was originally named as a TSH-releasing hormone, there is now considerable evidence that TRH is involved in speciesspecific hypophysiotropic functions. The levels of TRH in several species
http://dx.doi.org/10.1016/j.npep.2015.08.001 0143-4179/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: Kanasaki, H., et al., Role of thyrotropin-releasing hormone in prolactin-producing cell models, Neuropeptides (2015), http://dx.doi.org/10.1016/j.npep.2015.08.001
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of fish, such as carp, tilapia and African lungfish, are not capable of stimulating TSH (Kagabu et al., 1998; Melamed et al., 1995; Gorbman and Hyder, 1973). In other types of fish, TRH exerts a modest effect on TSH stimulation, and corticotropin-releasing hormone (CRH) seems to play the role of a TSH-releasing factor, at least in coho salmon (Larsen et al., 1998). Indeed, in amphibians, CRH appears to be the major TSHstimulating factor (Okada et al., 2009). TRH is known to stimulate the secretion of growth hormone (GH) in carp (Kagabu et al., 1998) and is a potent stimulator of α-melanocyte-stimulating hormone in teleost fish (Tran et al., 1989). TRH is also a potent stimulator of prolactin secretion in amphibians (Castano et al., 1993) and is the major prolactinreleasing factor in the hypothalamus of the bullfrog (Nakajima et al., 1993). In the pituitary in mammals, TRH stimulates not only TSH, but also prolactin and GH (Szabo et al., 1984; Tashjian et al., 1971). 3. TRH as a prolactin-releasing factor Shortly after its initial identification as a TSH-releasing factor, TRH was shown to cause the rapid release of prolactin from rat anterior pituitary cells (Tashjian et al., 1971). However, it is not clear whether TRH is a physiological regulator of prolactin. Indeed, a number of different experimental approaches have failed to clarify the physiological role of TRH. In humans, the same concentrations of TRH that release TSH also release prolactin (Noel et al., 1974). In rats, the neutralization of endogenous TRH with TRH antisera suppresses the basal secretion of prolactin (Koch et al., 1977), and suckling causes an increase in hypothalamic and portal TRH levels along with a decrease in dopamine levels (de Greef et al., 1981). In human hypothyroidism, basal levels of TSH and prolactin, as well as their response to TRH, are increased (Snyder et al., 1973). On the contrary, immunoneutralization of TRH did not affect the magnitude of prolactin release in proestrus rats (Horn et al., 1985). TRH knockout mice displayed hypothyroidism with elevated TSH but had normal prolactin levels (Yamada et al., 1997). However, observations of TSH levels during lactation and the evaluation of prolactin levels in various thyroid states suggest that TRH is a physiological prolactin-releasing factor, albeit not the primary factor or one of major importance. 4. Rat pituitary somatolactotroph GH3 cell line Pituitary somatotrophs and lactotrophs are both acidophilic cells and are believed to derive from the same origin. In the anterior pituitary gland of normal adult rats, acidophilic cells are almost equally divided into somatotrophs, lactotrophs and somatolactotrophs (Frawley et al., 1985). Somatolactotrophs, however, appear earlier than somatotrophs and lactotrophs during neonatal development in rats, and the proportion of lactotrophs has been reported to be only 1.7% of all anterior pituitary cells (Hoeffler et al., 1985). These observations suggest the possibility that prolactin-secreting cells arise from GH-secreting cells. GH3 cells, established from rat pituitary adenoma, can synthesize and secrete both prolactin and GH, and exist as either somatotrophs or somatolactotrophs (Boockfor and Schwarz, 1988). Thus, GH3 cells are widely used as a model to study the functions of normal pituitary acidophilic cells. 5. Intracellular signaling evoked by TRH in GH3 cells It is known that TRH stimulates production of inositol phospholipid by activating the Gq protein-coupled TRH receptor in lactotrophs. This in turn stimulates the protein kinase C pathway (PKC) and Ca2+ release from Ca2+ storage sites (Gershengorn, 1986). TRH-induced signaling activates the extracellular signal-regulated kinase (ERK) via PKCdependent and PKC-independent pathways—the former pathway activates MEK kinase (MEKK) via PKA and the latter induces Rasdependent MEKK activation via tyrosine phosphorylation of Shc proteins. MEKK activates MEK by phosphorylation and ultimately ERK is
activated by MEK (Winitz et al., 1993; Ohmichi et al., 1994). TRHinduced ERK activation is inactivated via dephosphorylation by dual specificity protein phosphatases, MAP kinase phosphatases (MKPs) (Oride et al., 2009). On the other hand, the elevation of intracellular Ca2 + levels from Ca2 + storage sites, via the mobilization of inositol phospholipid or the influx of extracellular Ca2 + through calcium channels, activates Ca2 +-dependent protein kinases such as Ca2 +/ calmodulin-dependent protein kinase II (Jefferson et al., 1991; Cui et al., 1994). 6. TRH signaling and prolactin synthesis/secretion The TRH-induced release and synthesis of prolactin are regulated by different signaling cascades. The TRH-induced activation of ERK is strongly involved in prolactin gene expression, as shown by the expression of TRH-induced prolactin mRNA being completely inhibited in the presence of a MEK (an activator of ERK) inhibitor (Kanasaki et al., 1999, 2002). In addition, overexpression of the constitutively active form of MEKK increases the expression of endogenous prolactin mRNA (Kanasaki et al., 2002). These observations are explained by the fact that the prolactin promoter contains binding sites such as Ets-1 and GFH-1/Pit-1, both of which synergistically enhance the synthesis of prolactin in a Ras/Raf response element within the prolactin promoter that is related to ERK signaling pathways (Bradford et al., 1995). However, the release of TRH-stimulated prolactin does not occur via ERK activation. The MEK inhibitor did not inhibit the release of TRH-induced prolactin, but it did inhibit it in the presence of the inhibitor for Ca2 +/ calmodulin-dependent protein kinase II or myosin light chain kinase, both of which are dependent upon Ca2+ for activation (Kanasaki et al., 1999, 2002). These observations clearly demonstrate that hormone release and synthesis are regulated differently by TRH stimulation. In GH3 cells, both prolactin and GH are regulated by TRH stimulation; GH synthesis is reduced by TRH, whereas prolactin synthesis is stimulated (Kanasaki et al., 2002). Previous studies have demonstrated that treating GH3 cells with TRH results in an increased number of prolactin-producing cells and a decreased number of GH-secreting cells (Boockfor et al., 1985; Schonbrunn et al., 1980). Epidermal growth factor (EGF) has an effect similar to that of TRH as it increases prolactin and decreases GH levels in GH4Cl cells, a subclone of GH3 cells (Schonbrunn et al., 1980). TRH-induced ERK activation is strongly involved in this phenomenon as the inhibition of ERK does not increase prolactin synthesis but increases GH synthesis. In addition, overexpression of the constitutively active form of MEKK decreases GH synthesis (Kanasaki et al., 2002). If an increasing population of prolactin-producing cell was in the more differentiated stage among somatolactotrophs, it is possible that TRH could act as a differentiation-promoting factor, leading to a decrease in the proportion of somatotrophs and an increase in the proportion of lactotrophs. The proposed mechanisms of TRH action in hormone synthesis and release in GH3 cells is shown in Fig. 1. 7. Mode of TRH delivery and the effect on prolactin expression It is well known that hypothalamic gonadotropin-releasing hormone (GnRH) is delivered into portal circulation in a pulsatile manner and its pulse frequency determines predominant output of pituitary gonadotropins, namely luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Crowley et al., 1985). The release of GnRH needs to be in a pulsatile manner, and not continuous, to maintain the secretion of gonadotropins (Knobil, 1980). In addition, a more rapid pulse frequency of GnRH predominantly increases the secretion of LH, whereas a slower pulse frequency of GnRH decreases LH secretion and increases FSH release (Wildt et al., 1981). As for TRH, its secretion was found to be episodic and irregular in the venous blood of the pituitary in mares (Alexander et al., 2004), whereas in humans TRH is released in a pulsatile manner with regard to frequency and amplitude (Adriaanse et al.,
Please cite this article as: Kanasaki, H., et al., Role of thyrotropin-releasing hormone in prolactin-producing cell models, Neuropeptides (2015), http://dx.doi.org/10.1016/j.npep.2015.08.001
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Fig. 1. Schematic summary of the role of TRH in somatolactotroph GH3 cells. TRH binds to the Gq protein-coupled TRH receptor and induces Raf (MEKK) activation via PKC-dependent and -independent pathways. ERK is activated through MEKK/MEK activation and increases prolactin gene expression. ERK activation is also involved in growth hormone (GH) inhibition as well as cell growth inhibition, whereas intracellular Ca2+ from intracellular Ca2+ storage sites or extracellular sites activates Ca2+-dependent protein kinases, such as calcium/calmodulin-dependent kinase II (CaML II) or myosin light chain kinase (MLCK), that accelerate both prolactin and GH release.
1992). These observations suggest that circulating TRH levels are not continuously maintained, but TRH is released as a hormonal pulse. We previously examined how pulsatile TRH affects somatolactotroph GH3 cells and the transcriptional activity of prolactin promoters. Experiments were performed using a perifusion system to perifuse TRH in a pulsatile manner, and pulsatile TRH stimulation at 30-min intervals increased prolactin promoter activity in a similar manner to that following continuous TRH stimulation. In addition, we found that a higher TRH pulse frequency (1 pulse/30 min) was more effective in obtaining maximal activity compared with a low TRH pulse frequency (1 pulse/120 min) (Oride et al., 2008). These findings suggest that an increased exposure of cells to TRH results in an increased production of prolactin. Although ERK activation induced by TRH is strongly involved in prolactin synthesis as described above, the strength or duration of ERK activation is not correlated with prolactin promoter activity in experiments using a static culture. In addition, it seems that transient occupation of the TRH receptor is important to initiate the stimulation of prolactin promoter activity in static conditions as the prolactin promoter activity was similar when cells were exposed to TRH for 10 min or for 6 h (Oride et al., 2008). 8. Interaction of TRH and adenylate cyclase-activating polypeptide in lactotrophs Pituitary adenylate cyclase-activating polypeptide (PACAP) is a hypothalamic peptide that affects lactotroph functionality. PACAP was
originally isolated from ovine hypothalamic extracts on the basis of its ability to stimulate cAMP in anterior pituitary cells (Miyata et al., 1989). Although PACAP was first reported to lack prolactin-releasing activity in cultured rat adenohypophyseal cells (Hart et al., 1992), later studies showed that prolactin release from rat pituitary cells can be slightly increased by treatment with PACAP (Arbogast and Voogt, 1994; Jarry et al., 1992). PACAP receptors are expressed in all cell types of rat adenohypophysis (Rawlings and Hezareh, 1996), and pituitary lactotrophs predominantly express the PACAP type I receptor (PAC1R) (Vertongen et al., 1995). We have previously shown that PACAP can stimulate prolactin gene expression in a lactotroph cell model, although the effect was limited compared with TRH stimulation. If cells adequately express PAC1R by overexpressing PAC1R, the response of prolactin promoters to PACAP was similar to the response to TRH. In addition, PACAP potentiates the effect of TRH on prolactin expression. Interestingly, overexpression of cellular PAC1R increases the basal levels of transcriptional activity of the prolactin promoter as well as the TRH-induced prolactin promoter activity (Mijiddorj et al., 2011), suggesting that both the TRH receptor and PAC1R cooperate with each other and produce more prolactin. Prolonged stimulation with TRH desensitizes its own TRH receptor and the response of prolactin promoters to TRH is eliminated. Furthermore, the response of prolactin promoters to PACAP is also eliminated by prolonged pretreatment with TRH. On the other hand, prolonged treatment with PACAP desensitizes PAC1R in the cells and the response of prolactin
Please cite this article as: Kanasaki, H., et al., Role of thyrotropin-releasing hormone in prolactin-producing cell models, Neuropeptides (2015), http://dx.doi.org/10.1016/j.npep.2015.08.001
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promoters to PACAP is eliminated, while the response of prolactin promoters to TRH is also eliminated by prolonged pretreatment with PACAP (Mijiddorj et al., 2013). These findings demonstrate that sustained stimulation with TRH and PACAP desensitizes their own and each other's receptors. Addition to the PACAP, hypothalamic peptide, cocaine- and amphetamine-regulated transcript (CART), has been reported to responsible for reduce TRH-induced prolactin release (Raptis et al., 2004). 9. Conclusions Since TRH was discovered 45 years ago, a substantial amount of information about its role has been accumulated. TRH is the principal hypothalamic factor that stimulates the release of TSH from the anterior pituitary in vertebrates and it is also known as a prolactin-releasing factor. In this review, we have summarized our understanding of the action of TRH in the pituitary lactotroph cell model involving GH3 cells. TRH exerts multiple species-dependent hypophysiotropic activities and a divergent effect on prolactin and GH in somatolactotroph cell models. TRH may interact with other neuropeptides, such as PACAP, at the receptor level. Novel information could be obtained by further studies involving TRH. References Adriaanse, R., et al., 1992. Circadian changes in pulsatile TSH release in primary hypothyroidism. Clin. Endocrinol. (Oxf) 37 (6), 504–510. Alexander, S.L., Irvine, C.H., Evans, M.J., 2004. Inter-relationships between the secretory dynamics of thyrotrophin-releasing hormone, thyrotrophin and prolactin in periovulatory mares: effect of hypothyroidism. J. Neuroendocrinol. 16 (11), 906–915. Arbogast, L.A., Voogt, J.L., 1994. Pituitary adenylate cyclase-activating polypeptide (PACAP) increases prolactin release and tuberoinfundibular dopaminergic neuronal activity. Brain Res. 655 (1–2), 17–24. Boockfor, F.R., Schwarz, L.K., 1988. Cultures of GH3 cells contain both single and dual hormone secretors. Endocrinology 122 (2), 762–764. Boockfor, F.R., Hoeffler, J.P., Frawley, L.S., 1985. Cultures of GH3 cells are functionally heterogeneous: thyrotropin-releasing hormone, estradiol and cortisol cause reciprocal shifts in the proportions of growth hormone and prolactin secretors. Endocrinology 117 (1), 418–420. Bradford, A.P., et al., 1995. Functional interaction of c-Ets-1 and GHF-1/Pit-1 mediates Ras activation of pituitary-specific gene expression: mapping of the essential c-Ets-1 domain. Mol. Cell. Biol. 15 (5), 2849–2857. Burgus, R., et al., 1970. Characterization of ovine hypothalamic hypophysiotropic TSHreleasing factor. Nature 226 (5243), 321–325. Castano, J.P., et al., 1993. Different exocytotic morphology in amphibian prolactin and growth hormone cells stimulated in vitro with TRH. Tissue Cell 25 (2), 165–172. Crowley Jr., W.F., et al., 1985. The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women. Recent Prog. Horm. Res. 41, 473–531. Cui, Z.J., Gorelick, F.S., Dannies, P.S., 1994. Calcium/calmodulin-dependent protein kinaseII activation in rat pituitary cells in the presence of thyrotropin-releasing hormone and dopamine. Endocrinology 134 (5), 2245–2250. de Greef, W.J., Plotsky, P.M., Neill, J.D., 1981. Dopamine levels in hypophysial stalk plasma and prolactin levels in peripheral plasma of the lactating rat: effects of a simulated suckling stimulus. Neuroendocrinology 32 (4), 229–233. Frawley, L.S., Boockfor, F.R., Hoeffler, J.P., 1985. Identification by plaque assays of a pituitary cell type that secretes both growth hormone and prolactin. Endocrinology 116 (2), 734–737. Gershengorn, M.C., 1986. Mechanism of thyrotropin releasing hormone stimulation of pituitary hormone secretion. Annu. Rev. Physiol. 48, 515–526. Gorbman, A., Hyder, M., 1973. Failure of mammalian TRH to stimulate thyroid function in the lungfish. Gen. Comp. Endocrinol. 20 (3), 588–589. Hart, G.R., Gowing, H., Burrin, J.M., 1992. Effects of a novel hypothalamic peptide, pituitary adenylate cyclase-activating polypeptide, on pituitary hormone release in rats. J. Endocrinol. 134 (1), 33–41. Hoeffler, J.P., Boockfor, F.R., Frawley, L.S., 1985. Ontogeny of prolactin cells in neonatal rats: initial prolactin secretors also release growth hormone. Endocrinology 117 (1), 187–195. Horn, A.M., Fraser, H.M., Fink, G., 1985. Effects of antiserum to thyrotrophin-releasing hormone on the concentrations of plasma prolactin, thyrotrophin and LH in the prooestrous rat. J. Endocrinol. 104 (2), 205–209. Iversen, E., Weeke, J., Laurberg, P., 1984. TRH immunoreactivity in the thyroid gland. Scand. J. Clin. Lab. Invest. 44 (8), 703–709. Jarry, H., et al., 1992. Contrasting effects of pituitary adenylate cyclase activating polypeptide (PACAP) on in vivo and in vitro prolactin and growth hormone release in male rats. Life Sci. 51 (11), 823–830. Jefferson, A.B., Travis, S.M., Schulman, H., 1991. Activation of multifunctional Ca2+/ calmodulin-dependent protein kinase in GH3 cells. J. Biol. Chem. 266 (3), 1484–1490.
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Please cite this article as: Kanasaki, H., et al., Role of thyrotropin-releasing hormone in prolactin-producing cell models, Neuropeptides (2015), http://dx.doi.org/10.1016/j.npep.2015.08.001