Hormone Action PDF

Hormones, Classification and Mechanisms of action Dr Solomon Genet Endocrinology: General concepts What are hormones? What is an endocrine gland? How do we classify hormones? How are hormones made? How are hormones released and transported? How do hormones act on a targ...

Hormones, Classification and Mechanisms of action Dr Solomon Genet Endocrinology: General concepts What are hormones? What is an endocrine gland? How do we classify hormones? How are hormones made? How are hormones released and transported? How do hormones act on a target organ?  What is a hormone? A hormone is a chemical messenger released from a cell to influence the activity of the same or of another cell via a receptor Endocrine cell Target cell signal hormone receptors Blood vessel  Types of endocrine system Endocrine gland A well-defined collection of endocrine cells Neuroendocrine systems Neurons that release hormones into the blood and CNS Diffuse endocrine systems Endocrine cells not arranged in glands but dispersed  Endocrine communication Endocrine communications can be of three types: autocrine (where the hormone is produced and acts on the same cell) or paracrine (hormone produced in one cell but acts on another cell), endocrine if the hormone is synthesized in an endocrine gland but travels through blood a long distance Paracrine Autocrin e Endocrine  Endocrine glands Biochemistry, Mathews et al.  Functions of endocrine systems Promote survival of organisms by effects on: Development, growth and differentiation Maintaining a stable internal environment ‘homeostasis’ Responding to an altered external environment Control of reproduction  How quick are endocrine actions?2A Depending on the type of hormone endocrine systems act differently Rapid (secs - mins) Intermediate (mins) Prolonged (hours, days)  Adrenaline release in stress FAST ACTING ‘fight or flight’ response Also called as Epinephrine It has its effect in seconds  Insulin release in response to a meal INTERMEDIATE Acting Effect of insulin prevails in a few minutes Lung development just before birth SLOW Normal No surfactant surfactant CORTISOL from fetal adrenal causes the production of surfactant  Hormones are released in pulses Prolactin and growth hormone Hormones are released in pulses and the pattern of pulses varies for different hormones  Diurnal rhythms: pulses vary during the day ACTH and cortisol cortisol When hormone release has two phases in the day it is described as diurnal. ACTH and cortisol are hormones that display this pattern.  Feedforward and feedback control of Hormone action - ve Stimulus Hypothalamus Inhibitory Releasing hormone feedback Feedforward control - ve Anterior pituitary Trophic hormone Endocrine gland e.g. cortisol release from adrenal Target Cellular function  Chemical classes of hormones Based on their chemical nature and their interaction with water, hormones are classified into two Hydrophilic Hydrophobic  Hydrophilic class of hormones EXAMPLE 1) Protein hormone Insulin 2) Glycoprotein hormone Luteinising hormone 3) Amine hormone Adrenaline 4) Iodothyronines (Thyroid Thyroxine hormone)  Biosynthesis, storage and release of protein hormones Rough endoplasmic reticulum  Regulated release Proteins concentrated and stored in secretory granules Many granules stored in the cell Released quickly in response to a stimulus Constitutive release Granules are not stored in cell Released as soon as produced Protein hormones are produced as ‘prohormones’ Protease pre-prohormone cleavage Rough ER signal peptide prohormone Golgi active hormone Secretory granule Example Insulin -  Production of several hormones from one prohormone Example - Proopiomelanocortin (POMC) POMC PROTEIN MSH ACTH lipotropin endorphin In some cases many hormones are produced from a single protein as indicated in the above example.  Prohormones can contain several copies of the same hormone Example - pro thyrotrophin releasing hormone (TRH) TRH TRH TRH TRH TRH TRH It is also possible that a prohormone may be produced with many Copies of the same hormone. Some endocrine cells produce more than one active hormone Produced from: The same prohormone eg ACTH and MSH from POMC in pituitary Different prohormones eg LH and FSH in pituitary reproductive cells  Amine hormone synthesis noradrenaline Dopamine hydroxylase L-dopa Dopa decarboxylase dopamine adrenaline  Hydrophobic class of hormones EXAMPLES Cholesterol Steroid hormones derivatives Arachidonic prostaglandins acid derivatives NB: These are water insoluble hormones. Steroids Testes Testosterone Ovary Estrogen Progesterone Adrenal Cortisol Aldosterone  Steroid hormone synthesis Made rapidly from cholesterol via enzymes in mitochondria and smooth ER, not stored Mitochondria Lipid stores Smooth ER Prostaglandin synthesis Prostaglandin E2 Prostaglandin F2 Prostaglandin I2  Release of hormones Small hydrophobic hormones diffuse Hydrophilic hormones are released by the exocytosis of secretory granules  Storage of hormones ▪ Amines and proteins are stored in large amounts in secretory granules ▪ Some proteins are not stored (growth factors, cytokines) ▪ Steroids are produced on demand and released as produced  Transport of hormones in blood Hydrophilic hormones can circulate freely in plasma Most steroid and thyroid hormones are bound to specific binding proteins in the plasma Binding of hormones reduces their clearance and thus extends the ‘half-life’ Metabolism and excretion of hormones Hormones internalized with their receptor are degraded in lysosomes Steroid hormones are degraded in the liver Hormones are also lost by excretion through the kidneys 10 minutes break  Hormone action Endocrine cell Target cell signal hormone receptors Blood vessel  Hormone receptor action What is a receptor? What are the main classes of receptor? What intracellular signals are activated? How are receptor signals turned off? Characteristics of hormone receptors High affinity for hormone Hormone specificity Binding is saturable  Hormone response and binding curves Amount Kds bound 10-12 –10-9 [hormone] log [hormone] Response Concn that gives e.g. 50% response exocytosis = EC50 log [hormone]  Receptor classes There are four types of receptors Type 1 : Ligand-gated channels Type 2: G protein-coupled receptors Type 3: Enzyme-linked (Tyrosine kinase) receptor Type 4: Intracellular receptors Note that receptor types 1 – 3 are membrane receptors Receptor type 1 (Ligand gated receptors) Direct control of an ion channel Hormone/ ions neurotransmitter R depolarisation/hyperpolarisation Cell function timescale: millisecs eg: nicotinic Ach receptor at NMJ  Receptor type 2 G protein-coupled receptors Hormone R Enzyme G second messengers timescale: secs cell function G proteins are involved in responses to the majority of hormones Protein hormones e.g. glucagon Amine hormones e.g. adrenaline Lipid derived e.g. prostaglandins  Structure of G protein-coupled receptors N ter Serpentine shape outside plasma membrane inside glycosylation phosphorylation C ter  The G protein is heterotrimeric outside inside GDP α G protein is made of 3 subunits γ β It spans the membrane Gs seven times Gi Gq  G Proteins G proteins get their name from their ability to bind GTP and GDP They exist in an active (GTP bound) and an inactive (GDP bound) form Active G proteins bind and activate ‘signalling’ enzymes causing a specific response Serve as signal transducers but not enzymes The G protein cycle  Downstream effectors The release, receptor binding and signal transduction will activate intracellular effectors like enzymes, transporter proteins and second messengers. Some downstream effectors are indicated below. Adenylate cyclase Phospholipase C Ion channels G protein control of adenylate cyclase Hormone Hormone R R Gs adenylate Gi cyclase +ve -ve ATP cyclic AMP (cAMP) degraded by activates phosphodiesterase protein kinase A 5’ AMP R C C R C C protein phosphorylation/ activation cAMP in adrenal cortex cells stimulates steroid hormone synthesis ACTH R Gs adenylate cyclase cholesterol ester ATP cyclic AMP cholesterol ester hydrolase + cholesterol activates mitochondrial protein kinase A cholesterol uptake +  G protein activation of phospholipase C Hormone L R PLC diacylgycerol (DAG) Gq PIP2 activation of intracellular proteins protein kinase C inositol trisphosphate (IP3) calmodulin/Ca 2+ protein phosphorylation/ activation Ca2+ e.g. noradrenaline endoplasmic reticulum at 1 receptors  G proteins can also activate ion channels ions Hormone R G G Enzyme second messengers cell function e.g. exocytosis of TSH Reaction cascades cause massive signal amplification R Receptor G G G G G proteins Enzyme/ion channel 2nd messengers Protein kinases Target proteins  Receptor type 3: Enzyme-linked Receptor is also the effector enzyme (has catalytic role) Hormone Hormone R R Enzyme Enzyme Tyrosine kinase or guanylate cyclase enzyme activity in intracellular face of receptor  Receptor Type 3 Receptors dimerise on ligand binding Hormone Hormone R R Enzyme Enzyme protein phosphorylation timescale: minutes Cell function eg: insulin, EGF receptors Insulin Receptors insulin a a glucose Glut4 plasma membrane tyrosine kinase ser tyr tyr ser activation Glut4 Autophosphorylation of the receptor Skeletal muscle, Adipose cell  Receptor type 4 Control of DNA transcription - steroid hormones steroid plasma membrane steroid receptor control of gene protein transcription synthesis RE X gene X In nucleus Timescale - hours!  Steroid hormone action Lipid soluble steroids diffuse into cell Interact with intracellular receptors and receptors move to nucleus Interact with gene promotors at specific hormone response elements Up or down regulate transcription  Steroid receptor structure Transcriptional DNA Hormone regulation binding binding N ter C ter DNA strand contains specific hormone response elements  Intracellular receptors Hormone Receptor Androgens AR Estrogen ER Progesterone PR Glucocorticoids GR Mineralocorticoids MR Thyroid hormone TR  Turning off the signal The effect and signal of hormones can be halted as follows. Removal or degradation of the hormone Desensitisation of the receptor Internalisation of the receptor  Summary The endocrine system co-ordinates the body’s internal physiology, development and helps it to adapt to the external environment Hormones are chemical messenger released from a cell to influence the activity of same or another cell There are two major classes of hormones; hydrophillic and hydrophobic Hormones act by binding to receptors on target cells. There are four classes of hormone receptors: Ligand-gated channels, G protein-coupled receptors and enzyme-linked receptors are cell surface receptors steroid hormones receptors are intracellular receptors  END Tomorrow on Steroid hormones and Mineralocorticoids