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Neuroendocrinology Neuroendocrinology Neuroendocrinology Hypothalamus and Pituitary • Hypothalamus-pituitary unit is the most dominant portion of the endocrine system • Regulates the function of the – – – – – – Thyroid Adrenal Reproductive glands Controls somatic growth Lactation Water metabolism The pituitary releases hormones that induce or inhibit the release of other hormones The Hypothalamic-Pituitary unit Posterior pituitary (Neurohypophysis) • An outgrowth of the hypothalamus composed of neural tissue. • Hypothalamic neurons pass through the neural stalk and end in the posterior pituitary. • 2 Hormones are released (ADH) Anterior pituitary (Adenohypophysis) • AP is connected to the hypothalamus by the superior hypophyseal artery. Median eminence Releasing Hormones • The AP produces six hormones: • • • • • • Prolactin (PRL) Growth hormone (GH) Thyroid stimulating hormone (TSH) Adrenocorticotropic hormone (ACTH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) AP Hormone release Hypothalamic releasing hormones Hypothalamic releasing hormone Effect on anterior pituitary Corticotropin releasing hormone (CRH) Thyrotropin releasing hormone (TRH) Growth hormone releasing hormone (GHRH) Somatostatin Stimulates ACTH secretion Gonadotropin releasing hormone (GnRH) Prolactin releasing hormone (PRH) Prolactin inhibiting hormone (dopamine) Stimulates TSH and Prolactin secretion Stimulates GH secretion Inhibits GH (and other hormone) secretion Stimulates LH and FSH secretion Stimulates PRL secretion Inhibits PRL secretion Characteristics of hypothalamic releasing hormones • • • • • • Secretion in pulses Act on specific membrane receptors Transduce signals via second messengers Stimulate release of stored pituitary hormones Stimulate synthesis of pituitary hormones Stimulates hyperplasia and hypertophy of target cells • Regulates expression of its own receptor Hormones of the Anterior pituitary Hormones of the Anterior pituitary Hormones of the Anterior pituitary Hormones of the Anterior pituitary Hormones of the Anterior pituitary Regulation of endocrine axes HPA axis CRH ACTH Adrenals Cortisol Endocrine signalling - Hormones are synthesised and secreted by cells in endocrine glands - They enter bloodstream, are distributed throughout body and can act at distant target sites • Each hormone acts only on certain cells – Cells respond only when they have receptors for the hormone in question • Is slower than nervous system control • Endocrine and nervous system to interact with one another Endocrine signalling • All cells potentially exposed to all hormones via circulation • Only cells with specific receptor for specific hormone can respond • Because of dilution in blood stream, [hormone]blood are very low (10-9 mol.l-1; nM) • Receptors must bind hormones very effectively i.e. they must have a high affinity for the specific hormone 2 types of hormone receptors Steroid hormone Intracellular receptor Non-steroid hormone (peptide) Cell surface receptor Receptors & Downstream Signalling Receptors • 4 main types of receptor: – Ionotropic (Ion channel linked) – Metabotropic (G protein-coupled) – Kinase linked receptors – Intracellular receptors Transmembrane Receptors Ion channel receptors • Ligand-gated ion channels • Protein pores in the plasma membrane that open or close in response to a chemical signal. G-Protein-coupled Receptors cAMP as a 2nd messenger Gs • Neurotransmitter • Adrenaline acting at -adrenoceptors • Hormone • ACTH acting at ACTH receptors cAMP as a 2nd messenger Gs • Neurotransmitter • Adrenaline acting at -adrenoceptors • Hormone • ACTH acting at ACTH receptors • Inhibitory regulation of adenylyl cyclase via receptors linked to Gi cAMP levels 2nd messengers - Small molecules that spread throughout the cell easily - Participate in pathways initiated by G-protein-linked receptors and tyrosine-kinase receptors. Most widely used: -Cyclic AMP -IP3/Calcium ions (Ca2+) Cyclic Adenosine Monophosphate (cAMP) Signal Amplification cAMP as a 2nd messenger • Neurotransmitter • Adrenaline acting at -adrenoceptors subunit can also activate ion channels directly • Hormone • ACTH acting at ACTH receptors subunit can also activate ion channels directly Specificity of cell signaling Cells can react differently to certain signals, because different kinds of cells have different collections of proteins. Cellular response to adrenaline in liver via -adrenoceptor activation Inositol trisphosphate signaling pathway Another 2nd messanger pathway PM PI is a phospholipid found in the plasma membrane IP3 and DAG as 2nd messengers (eg) Serotonin action at 5-HT2 receptors DAG activates protein kinase C Tyrosine-Kinase Receptors • Receptors with enzymatic (Kinase) activity – Phosphorylate tyrosine residues • Examples – Insulin – Nerve Growth Factor – Cytokines such as IL-6, IL-10, IFN- • Steps in receptor activation: • Ligand binds causing the two receptor polypeptides to dimerize • Tyrosine kinase activation • Phosphorylation of tyrosine residues on the tail of the other polypeptides Protein phosphorylation cascades: A central mechanism of signal transduction • Protein kinase: an enzyme that transfers phosphate groups from ATP to a protein – Usually phosphorylate either serine, threonine or tyrosine residues – Abundant relay molecules in signal transduction cascades – Often phosphorylate each other • The signal is transmitted by a series of phosphorylations, each bringing with it a conformational change • Protein kinases are very important – Regulate a large number of the proteins in the cell • Protein phosphates: enzymes that remove phosphate groups from proteins – The effects of protein kinases are rapidly reversed in the cell by protein phosphates – Balance between kinases and phosphatases is important Signaling pathways into the nucleus • Some signaling pathways regulate the synthesis of enzymes or other proteins - not their activity. • Transcription factors control which genes are turned on. It’s activity may be regulated by a signaling pathway that extends into the nucleus Signal transduction can result in activation of a transcription factor Signal transduction can result in activation of a transcription factor Example cAMP – PKA - CREB Steroid hormone receptors: Mechanism of action Glucocorticoid (Cortisol) Altered gene expression Nucleus Cytoplasm The stages of cell-cell communication • Cell signaling can be spilt into four steps • Release of signalling molecule: – Neurotransmitter, hormone, growth factor released • Reception: – The target cell detects a signal coming from outside of the cell. – Usually occurs when the signaling molecule binds to a receptor – When the signal binds to the receptor protein, it’s changed in some way. This initiates the process of transduction. • Transduction: – The signal is converted to a form that can bring about a specific cellular response. – Normally requires a sequence of changes in a series of different molecules. – Molecules in the pathway often called relay molecules. • Response: – Transduced signal triggers a specific cellular response The stages of cell-cell communication using chemical messengers Mediator release Receptors types and signalling mechaisms: overview