Mechanism of Melatonin Stimulation of Growth Hormone Release Via Somatostatin Inhibition free essay sample

Mechanism of melatonin stimulation of growth hormone release via somatostatin inhibition Joseph Angelo Israel Peguit University of the Philippines in the Visayas Cebu College Natural Sciences and Mathematics Division Abstract Secretion of growth hormone is affected by two primary hormones: Growth hormone-releasing hormone and somatostatin. The former is the primary stimulant to promote growth hormone secretion while the latter is the primary inhibitor that prevents growth hormone secretion. Many studies have already shown that melatonin stimulates secretion of growth hormone via somatostatin inhibition but its mechanisms remain unknown. I hypothesized that melatonin inhibits somatostatin at transcription level through inhibition of important somatostatin transcription factors. I collected data from primary and secondary literature to acquire information on the target tissues, receptors and cellular mechanisms of melatonin. I collected information about somatostatin with emphasis on the mechanisms of its expression. Results showed that melatonin inhibits transcription of somatostatin through inhibition of Cyclic-adenosine monophosphate response element binding protein (CREB) which is a constituent of the transcription factors for somatostatin expression. I. Introduction Melatonin is a major secretion of the pineal hormone primarily involved in animal sleeping patterns. For such function, people have been taking melatonin pills over the counter to cure sleeping disorders. Approval from FDA on these melatonin pills is not yet available since the total function of this hormone has not been fully known. However, intensive researches have been going on trying to elucidate the entire function of this hormone. Full understanding on the physiology of this hormone may precede medical innovations as it can help us understand more of our development. One of the ecent discoveries on this hormone is its ability to act as an antioxidant at the same time attenuating the activity of antioxidative enzymes in the body. In connection to its major role of promoting sleep, its medical benefits provide insights to the physiological process happening at the body while at sleep. It has been established that Growth hormone is produced by the anterior lobe of the pituitary gland. It is primarily stimulated by Growth hormone-releasing hormone and primarily inhibited by somatostatin. Secretion of the growth hormone promotes uptake of amino acids, metabolism of fats and bone formation. II. Methodology I collected results from various primary and secondary literatures available online. I selected and analysed a total of thirty-three primary and secondary literatures. In my analysis, I considered the specific tissues that were studied since results do differ even if methodologies are the same. I collated the results obtained through establishing connections to form a cohesive explanation on the mechanism of melatonin to inhibit somatostatin. Nonetheless, all my results are hypothetical as for the moment until physical experimentation must be done. III. Discussion Melatonin Properties It is widely accepted that melatonin (MT) is a neurohormone that is the key regulator of biological rhythms. Intensive study on MT after its discovery demonstrated that it is involved also in, genital development[1], pigment metabolism[8], immune response, neutralization of free radicals[2,3], cell growth and proliferation[4]. The chemical structure of melatonin renders it both lipophilic and partially hydrophilic[7,10]. Such property is very crucial since its transport to different parts of the body does not need specialized mechanisms[7]. MT synthesis primarily occurs in the pineal gland and it has been established that cells from the gastrointestinal tract, retina, ciliary body, lens, Harderian gland, brain, thymus, airway epithelium, bone marrow, gut, ovary, testicle, placenta, lymphocytes and skin altogether produce substantial amounts of melatonin. It exert influences the activity of other tissues via the bloodstream. Biosynthesis The primary production of melatonin occurs in the pineal gland. Synthesis and secretion of melatonin is activated by darkness and suppressed by light. The photic inputs from the retina travel via the retino-hypothalamic tract to the suprachiasmatic nucleus (SCN) of the hypothalamus, then to the superior cervical ganglion and finally to the pineal gland[5,10]. Tryptophan is the main amino acid needed for melatonin production. Melatonin production is a secondary product from serotonin. Serotonin is acted upon by N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) to form melatonin. Among the reactions, NAT is considered to be the rate limiting step in the formation of MT. Figure 1 Biosynthetic pathway of Melatonin Synthesis (Tan et. l 2006) or [9] Metabolism Melatonin must be converted to a more hydrophilic form since it is more of lipophilic than is hydrophilic[7,10]. It is then excreted via the kidneys after conversion[10]. The major catabolism of MT happens in the liver. Figure 2 catabolism of melatonin in Liver (Tan et. al 2006) or [9] Melatonin Receptors The receptors for melatonin had already been characteri zed. The subtype Mel1a dominates the receptors found in the SCN[6]. Though the pattern of receptor distribution varies from species to species but in general mammals contain fewer types of receptors than non-vertebrates [7,8]. The types of receptor expressed are Mel 1a (MT1) and Mel 1C [8]. The Pars tuberalis of the pituitary gland also contains a high density of the receptor. However, in humans the receptors are concentrated much on the SCN but are absent in the pars tuberalis (PT)[7,9,10]. This means that any regulation of melatonin on other hormones happen mostly in the SCN in the hypothalamus. The receptors of melatonin belong to the Gi/Go type of the superfamily of G-Protein Coupled Receptors (GPCR)[8]. The G-proteins are coupled to a number of effector systems influencing the intracellular signalling. They are designated as Gi/Go type because of their characteristic being inhibited by the presence of pertussis toxin[8]. Transduction Pathway The effector systems coupled to the melatonin receptors include the Adenylate cyclase, phospholipase C, L-type calcium channels, and ATP-sensitive K+ ion channels[8,6,33]. The inhibition of calcium influx via the L-type calcium channels may be mediated by direct inactivation by the G-protein[6] and/or through induced hyperpolarization by activation of ATP-sensitive K+ channel[6]. Activation of the G-proteins results to activation of ATP-sensitive K+ channels. The active transport of K+ ion intracellularly results to hyperpolarization of the membrane. The hyperpolarization inactivates the voltage-sensitive L-type Ca2+ channels which only opens during membrane depolarization[8,6]. Melatonin receptor activation inhibits activity of Phospholipase C (PLC)[8]. PLC functions to catalyze hydrolysis of phosphatidyl inositol (4,5) bisphosphate to Inositol triphosphate (IP3) and Diacyglycerol (DAG). Inositol triphosphate then functions to activate the IP3-dependent calcium channels in the endoplasmic reticulum to release Ca2+ to the cytosol. On the other hand, DAG activates of Protein Kinase C(PKC)[8,11, 12]. Some studies also showed melatonin can potentiate PLC [12]. In this case, dimerization of G-proteins is to be accounted. Different GPCRs can be expressed in a particular cell type where they can act independently, synergistically or antagonistically [13,14,15]. Recent studies have shown dimerization do not just occur among specific types of GPCRs but also among different types of GPCRs [13,14,15]making the understanding of GPCR signalling pathway even more complicated to understand. What is common among all pertussis-toxin sensitive GPCRs so far studied is their inhibition of adenyl cyclase (AC). Melatonin can inhibit AC by acting upon Gi/Go proteins but its possible though uncertain that dimerization of this type of GPCR with other types can result to AC activation. Activation of adenyl cyclase leads to the increase of cyclic-adenosine monophosphate (cAMP) that is crucial in expression of certain genes. [6,8] Illustration1: Shown is the pituitary transduction pathway of melatonin. Subsequent effects of melatonin on secondary messengers may affect both transcription and secretion of cellular products. The minus sign mean inhibition while a plus sign mean activation. Comparison of Melatonin Pathways in two target organs Pituitary Pathway The primary pathway of melatonin action exhibited in pituitary cells is shown in Figure 1. The differences of the effects of melatonin between pituitary cells and the SCN is due to the differences of GPCR types found between the two tissues. The PLC is inhibited in the pituitary pathway while it is activated in the SCN pathway. Activation is brought about by interactions of Gi/Go and Gq GPCRs on PLC. [16,17] Hypothalamic Pathway via SCN Illustration 2: This is the major pathway of melatonin action in SCN. Major difference from that of the Pituitary pathway is the activation of PLC. Its activation results in the subsequent activation of PKC and release of intracellular Ca2+. These two events may influence the activities of the cell including gene transcription and release of hormones and neurotransmitters. The SCN is the center of melatonin action. Multiple pathways occur at this region at different temporal stages. The PKC activation is known to occur during the dusk and dawn [18] which means that PKC activation in SCN is light-dependent. The activation of PKC proceeds to the activation of circadian rhythmicity, which accounts the importance of its activation in the tissue [18]. SitecAMPINsP3DAG/PKCCalciumCREB SCN-+++- Rat Hypothalamus- Rat Pituitary- Ovine Pituitary Somatostatin Inhibition by Melatonin via the Hypothalamic Pathway Somatostatin Somatostatin (SST) is a small cyclic peptide expressed in the different sites of the body but primarily expressed in the hypothalamus [19]. SST formation starts by proteolytic processing of larger precursor molecules which is the prepro-SS and pro-SS. The cleavage of pro-SS molecules results in the formation of two active forms of SS: SS-14 and SS-28 [19]. Five SSTreceptor (SSTr) subtypes are known to bind to SST. It is important to note that SSTreceptors, like melatonin receptors are coupled specifically to Gi’Go type of G proteins. The cellular mechanisms of SSTreceptor activation include adenylate cyclase inhibition, and prevention of calcium influx in pituitary cells[11]. The action of somatostatin in pituitary cells make it the primary inhibitor of Growth hormone release. Somatostatin inhibition on Growth hormone release Studies have shown that the mechanism of Somatostatin inhibition on GH release is not on transcription level but on the transport of the GH to the extracellular environment[20]. This suggests that the somatostatin influences its effect by changing the intracellular environment to prevent GH release. SST binding to its receptors especially SStr2 lead to the decrease of intracellular calcium concentrations and inhibit transcription of CREB, Protein Kinase and Adenyl Cyclase. In the inhibition of Adenyl Cyclase, intracellular cAMP levels decrease. The subsequent decrease of cAMP lead to the deactivation of Na+ permeable ion channels thus, preventing depolarization. Without depolarization along with inhibition of L-type Ca channels, influx can not happen thus preventing GH secretion via exocytosis. [21] Hypothesis of Melatonin inhibition on Somatostatin Production It has been shown in several studies that melatonin can stimulate GH release via inhibition of somatostatin [20,22,23 ]. It is suggested that the pathway for somatostatin inhibition is via hypothalamic pathway [20] due to the abundance of somatostatin receptors in the tissue. The mechanism of inhibition is not known in any literature found. Thus, it is a point in this section to trace the main effects of melatonin on the secondary messengers in SCN of hypothalamus. Melatonin’s mode of inhibition is on transcription level or on transportation level. Nonetheless, I contend that melatonin’s inhibition may be possibly at transcription level. Melatonin can possibly affect inhibition of somatostatin in two ways. It can affect by increasing the SST receptor-effector system [20] and /or affecting transcription of somatostatin by inhibition of important transcription factors needed for transcription of somatostatin. Via SST receptor-effector system The sst receptors and the G-proteins coupled to them constitute the receptor system of SST. While the effector system is composed of the various effects of the activation of the G-proteins caused by the binding of the ligand on the sst receptors. Both melatonin and somatostatin receptors are of Gi/Go type of GPCR as characterized by their sensitivity to Pertussis toxin. A possible mechanism that melatonin can attenuate the SST receptor-effector system is through dimerization. Melatonin coupling to its receptors may induce somatostatin-like intracellular effects since the same type of G-proteins are acted upon. Somatostatin has been proven to inhibit its own transcription through a negative feedback loop though no literature on its mechanism has been found yet. The mechanism of the negative feedback may be the same mechanism of melatonin on inhibition. One study showed that somatostatin can also inhibit CREB along with cAMP and Protein Kinase A [25]. The inhibiton of CREB, which is one of the transcription factor for SST transcription may mediate the negative feedback[26]. Via Inhibition of transcription factors needed for somatostatin expression Not much literature of the mechanism of somatostatin secretion is present. It is possible that the effect of melatonin on the secondary messengers influence SST expression. Camp-response element binding protein (CREB) is an important component for SST transcription to proceed. [25,26,27] CREB is constitutively bound to cAMP-response element (CRE), an enhancer of SST gene. Calcium concentrations, cAMP and Nitric Oxide influence CREB phosphorylation[26,28,29]. The CREB phosphorylation recruits CBP, a Histone Acetyl transferase (HAT) which will initiate assembly of basal transcription factors[27, 30]. Phosphorylation of CREB can be induced by Mitogen-activated protein kinase (MAPK) [28] and by Protein Kinase A (PKA) [30]. MAPK-induced phosphorylation may occur at the serine 142 residue. Phosphorylation at this region results in the separation of CREB from SST-CRE and transcription is unable to proceed [31,32]. However, phosphorylation of CREB at the serine 133 residue via protein kinase A result to transcription[31]. The MAPK pathway is activated by the influx of calcium [30] while PKA is activated by increase in cAMP levels[30]. Conclusion The action of melatonin is best manifested in pars tuberalis of the pituitary and the suprachiasmatic nucleus of the hypothalamus owing to the high density of melatonin receptors expressed. Differences in the action of melatonin between the pituitary and hypothalamus is attributed to differential activation of melatonin receptors on G-proteins. Melatonin receptors in SCN of hypothalamus activate both Gq and Gi/Go types of G-Proteins to activate PLC. While mel receptors in pituitary cells act via Gi/Go type only that results in inactivation of PLC. The somatostatin receptor, just like the melatonin receptors also belong the superfamily of G protein-Coupled Receptors (GPCR). Somatostatin receptors are also coupled to Gi/Go G-proteins just like mel receptors. I hypothesize that the similarity of the coupled G-proteins could explain the contention that melatonin attenuates the somatostatin receptor-effector system. I also hypothesize that the mechanism melatonin inhibition on somatostatin resembles that of the feedback regulation of somatostatin to itself. The possible regulation of melatonin on somatostatin synthesis may be at transcriptional level. This regulation may not be direct inhibition but induced through changes of the secondary messengers. Inhibition of melatonin on adenyl cyclase prevents phosphorylation of one of the transcription factors of Somatostatin gene. It is only through phosphorylation that CREB can assemble the basal transcription factors. Phosphorylation of CREB may be through Calcium-induced MAPK pathway of cAMP-dependent Protein Kinase A activation. However, the phosphorylation of CREB via MAPK pathway does not promote Somatostatin transcription due to different phosphorylation of residue.