Hypothalamic-pituitary system Bi1100en Hormones – Cellular and Molecular Mechanisms Hypothalamic-pituitary system Hypothalamus Pituitary gland (hypophysis) adenohypophysis neurohypophysis Pineal gland (epiphysis cerebri) Hypothalamo-hypophyseal system ▪ all vertebrates, human – size of about 4 cm3 ▪ in the midbrain, in contact with third ventricle ▪ infundibulum with pituitary gland ▪ part of the limbic system ▪ regulation of body temperature, food and water intake (hunger and thirst), reproduction, mood and emotions, circadian rhythms, controls the autonomic nervous system, mediate communication between nervous and endocrine system Hypothalamus ▪ hypothalamic nuclei > axonal transport > median eminence and transfer to the portal system (releasing factors) > adenohypophysis and other organs ▪ axonal transport to the neurohypophysis > store and release into the blood (oxytocin, vasopressin) Endocrine function of hypothalamus ▪ liberins (releasing factors) - thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH: LHRH and FSHRH), prolactoliberin (PRH), melanoliberin (MRH), growth hormone–releasing hormone (GHRH) ▪ statins (inhibiting factors) - somatostatin, follistatin, cortistatin ▪ dopamine (derived from tyrosine functions as prolactostatin) Releasing and inhibiting factors: synthesis ▪ peptidic hormones ▪ anterograde axonal transport (kinesins) ▪ released into the blood in median eminence Releasing and inhibiting factors: synthesis ▪ target cells in adenohypophysis ▪ signal transduction induced by one hormones can use multiple mechanisms, but the mail is usually only one of them GnRH, TRH: ▪ binds to G protein-coupled receptors > activation of IP3/DAG pathway > increase of intracellular Ca2+ > kinase activation (PKC) and cellular response GHRH, GHIH, CRH: ▪ binds to G protein-coupled receptors > activation of adenylate cyclase > cAMP > kinase activation (PKA) > phosphorylation of CREB transcription factors (cAMP response element-binding protein) and cellular response They stimulate or inhibit cells in the adenohypophysis, which produce tropic hormones > negative feedback loop. Releasing and inhibiting factors: mode of action Dopamine (DA, PIH) ▪ synthesis in hypothalamic neuron nuclei and partly in the adrenal glands ▪ catecholamine, tyrosine derivative ▪ binds to dopamine receptors and increases concentration of cAMP ▪ acts as a neurotransmitter and neurohormone that inhibits release of prolactin in the adenohypophysis Pituitary gland (hypophysis) ▪ glandotropic hormones (ACTH, TSH, FSH, LH) ▪ aglandotropic hormones (prolactin, GH) Tropic hormones (tropins): regulation ▪ half-life and degradation ▪ hypothalamic hormones (RH, IH) ▪ negative feedback (hormones produced by endocrine glands signal back to hypothalamus and hypophysis) ▪ peptide (191 AA) encoded by genes GH1 and GH2 ▪ homolog of prolactin and placental lactogen ▪ alternative splicing produces several GH isoforms ▪ released at intervals of 3 to 5 hours (maily after falling asleep) ▪ induced by GHRH, hypoglycemia, exercise, sleep ▪ transported by growth hormone binding proteins (GHBP) ▪ growth (anabolic) and stress hormone ▪ increases the concentration of glucose and free fatty acids in the blood, promotes the production of IGF-1 like growth factor (somatomedin C) in the liver Growth hormone (GH, somatotropin) ▪ targets all body organs ▪ especially the liver, bones and muscles ▪ growth, cell proliferation (mitogen), regeneration ▪ promotes erythropoietin production Growth hormone (GH, somatotropin) ▪ acts through growth factors called somatomedins (somatomedin C or insulin-like growth factor-1) from the liver Growth hormone (GH, somatotropin): pathophysiology ▪ gigantism ▪ acromegaly ▪ dwarfism ▪ metabolic inbalance (diabetes) Growth hormone (GH, somatotropin): recombinant hGH ▪ pre-pro-opiomelanocortin (285 AA) > proteolysis > pro-opiomelanocortin (POMC, 241 AMK) is the precursor of ACTH, melanotropin (MSH), βlipotropin, β-endorphin and others ▪ tissue specific posttranslational processing of POMC ▪ glycosylation, phosphorylation, acetylation, proteolysis by subtilisin-like enzymes ▪ half-life in blood approx. 10 min ▪ G protein-coupled receptors > cAMP > PKA ▪ rapid effect (minutes) - stimulation of cholesterol transfer to mitochondria (StAR, P450SCC) ▪ slow effect (hours) – stimulates the transcription of steroidogenic enzymes (e.g. P450SCC) and mitochondrial genes involved in oxidative phosphorylation ▪ ACTH is produced together with CRH in response to biological stress Corticotropin (Adrenocorticotropic hormone, ACTH) ▪ glycoprotein (201 AA; 26kDa): α subunit (92 AA) - related to human chorionic gonadotropin (hCG), follitropin and lutropin - stimulates adenylate cyclase and synthesis of cAMP β subunit (118 AA) - specific for TSH > receptor specificity Carbohydrate side chains ▪ half-life about one hour ▪ released in pulses and especially during a period of rapid growth and development ▪ receptors found primarily on thyroid follicular cells ▪ increases blood flow and metabolism in thyroid gland, stimulates synthesis of thyroxine and triiodothyronine Thyrotropin (Thyroid-stimulating hormone, TSH) Thyrotropin (Thyroid-stimulating hormone, TSH) ▪ gonadotropic hormone ▪ belons to the same structural group of hormones as TSH, FSH and hCG ▪ released in pulses ▪ half-life app. 20 minutes ▪ sex steroids suppress its production ▪ acts through cAMP ▪ triggers ovulation, corpus luteum development and progesterone production in women ▪ stimulates in Leydig cells to produce testosterone ▪ synergy with FSH Lutropin (Luteinizing hormone, LH) ▪ glycoprotein (35.5 kDa) ▪ structurally similar to LH, TSH and hCG (identical α subunit) ▪ half-life 3 to 4 hours ▪ gonadotropin interacting with LH ▪ acts through cAMP ▪ regulation of growth and development, sexual maturation and reproductive processes ▪ stimulates germ cell maturation in both males and females ▪ in Sertoli cells induces secretion of androgen-binding protein ▪ initiates growth of ovarian follicles (mitosis and production of follicular fluid) Follitropin (Follicle-stimulating hormone, FSH) ▪ homolog of growth hormone and placental lactogen ▪ peptide hormone with three disulfide bridges ▪ several isoforms (different molecular weight and glycosylation) > larger forms have lower biological activity ▪ secreted in pulses after eating, mating, estrogen administration, ovulation or when taking care of an offspring (activation of mechanoreceptors during breastfeeding + oxytocin) ▪ primarily inhibitory regulation by dopamine (PIH) secreted in hypothalamus ▪ endocrine, paracrine and autocrine effect (cytokine-like, hematopoiesis, angiogenesis) ▪ triggers mammary gland growth and lactation, modulates immunity, regulates growth and development in general ▪ maternal behavior, sexual refractory period, weak gonadotropin Prolactin (PRL, lactotropin) ▪ stimulates parental behavior, production of so-called pigeon milk in crop (pigeons), or esophagus (flamingos, penguins) ▪ together with estrogens involved in the physiological changes before nesting Prolactin (PRL, luteotropin): action and function Neurohypophysis (posterior pituitary) Hormones synthesized in hypothalamus and released to the blood in neurohypophysis. Superfamily of oxytocin and vasopressin neuropeptides ▪ produced in hypothalamus (nucleus paraventricularis and supraopticus), minor synthesis in corpus luteum, placenta, Leydig cells, retina, adrenal medulla, thyroid gland and pankreas ▪ production induced by cervical and uterine dilation during childbirt and stimulation of nipples during breastfeeding ▪ gene OXT encodes oxytocin/neurophysin I prepropeptide > enzymatic hydrolysis to end products ▪ nonapeptide with disulfide bridge: Cys-Tyr-Ile-Glu-Asp-Cys-Pro-Leu-Gly ▪ axonal transport to the neurohypophysis, where it is stored in vesicles (Herring bodies) with neurophysin I (10 kDa, 90-97 AA) and ATP ▪ stimulus > action potential in producer neuron > axonal depolarization > exocytosis of vesicles with oxytocin Oxytocin ▪ high affinity G protein-coupled receptors (rhodopsin-type, class I), e.g. on smooth muscle cells > IP3/DAG pathway > Ca2+ release > musle contraction ▪ sucking infant stimulates mother‘s mechanoreceptors > spinal nerves > hypothalamus > higher frequency of action potentials in oxytocin producing cells > release of oxytocin into the blood > mammary gland stimulation ▪ acts through peripheral nerves in the brain (hematoencephalic barrier) Oxytocin ▪ also referred to as arginine vasopressin (AVP) and argipressin ▪ differs from oxytocin in two AA (isoleucine/phenylalanine at position 3, leucine/arginine at position 8) ▪ supraoptical and paraventricular nuclei in the hypothalamus ▪ released during a decrease of blood pressure and blood volume, stimulated by angiotensin II through its receptors in the hypothalamus ▪ stored at the ends of axons (Herring bodies) separately from oxytocin and bound to the polypeptide neurophysin II (19.6 kDa, 95 AA) ▪ released in the neurohypophysis ▪ half-life 16-24 minutes Vasopressin / antidiuretic hormone (ADH) ▪ targets vasomotor activity and kidneys, (and brain > changes in behavior) ▪ V1 receptors (vascular smooth muscle) and V2 receptors (collecting ducts) Vasopressin / antidiuretic hormone (ADH) ▪ G protein receptor > cAMP > translocates aquaporins to the membrane of renal ducts (+ regulation of urea transporters) > decreased urine production > increased blood volume > higher arterial pressure Vasopressin / antidiuretic hormone (ADH) ▪ G protein receptor > IP3/DAG pathway > increase in arterial pressure ▪ physiological concentrations of ADH usually below vasoactive threshold (hemorrhagic shock) Vasopressin / antidiuretic hormone (ADH) Pineal gland (corpus pineale, glandula pinealis) ▪ similar to a pine cone ▪ in epithalamus between the two brain hemispheres in contact with the third cerebral ventricle ▪ calcificates during aging ▪ evolutionarily atrophied photoreceptor (in amphibians and reptiles associated with photoreceptor organs, parietal eye of the hateria) ▪ produces melatonin ▪ main regulator of circadian and seasonal rhythms ▪ N-acetyl-5-methoxy-tryptamine ▪ serotonin N-acetyl transferase ▪ produced also in plants (formed in response to oxidative stress) ▪ synchronizing hormone (melatonin receptor) and antioxidant (protection of nuclear and mitochondrial DNA) ▪ derived from tryptophan, synthesis via serotonin Melatonin (MT) ▪ passes through cell membranes ▪ in the dark: retinal photoreceptors > suprachiasmatic nuclei > spinal cord > sympathetic ganglia > norepinephrine stimulation > pineal gland > cAMP increase in pinealocytes > PKA > phosphorylation of serotonin N-acetyl transferase > conversion of serotonin to melatonin ▪ in the light: cessation of noradrenaline stimulation and rapid proteolysis of melatonin ▪ melatonin formation depends on the wavelength of light: blue light (460-480 nm) attenuates melatonin synthesis proportionally to the intensity and length of illumination Melatonin (MT) Synchronization of rhythms (circadian and seasonal): ▪ activity of nocturnal animals and sleep of diurnal species, including humans ▪ photoperiod and related in seasonal rhythms (behavior, reproduction, growth, color changes, etc.) Antioxidant: ▪ cytosolic and nuclear receptors > activation of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and glutathione reductase) ▪ effective scavenger of free radicals (cascading effect) ▪ involved in immune processes Melatonin (MT) Melatonin (MT) Melatonin