Major control systems of body 1. Nervous system 2. Endocrine system
• The endocrine system is the system of glands,each of which secretes different types ofhormonesdirectly into the bloodstream (some of which are transported along nervetracts)to regulate the body.
Word meaning• The endocrine system is in contrast to the exocrine system,• which secretes its chemicals using ducts.• It derives from the Greek words "endo" meaning inside, within, and "crinis" for secrete.
• The endocrine system is an information signal system• like the nervous system,• yet its effects and mechanism are classifiably different.• The endocrine systems effects are• slow to initiate, and• prolonged in their response,• lasting from a few hours up to weeks.
• The nervous system sends information very quickly, and responses are generally short lived.• Hormones are substances (chemical mediators) released from endocrine tissue• into the bloodstream• where they travel to• target tissue and generate a response.
• Hormones regulate various human functions, including• metabolism,• growth and• development,• tissue function,• and mood.
• In addition to the specialised endocrine organs mentioned above, many other organs that are part of other body systems, such as the kidney, liver, heart and gonads, have secondary endocrine functions.• For example the kidney secretes endocrine hormones such as erythropoietin and renin.
• The endocrine system is made of a series of glands that produce chemicals called hormones.• A number of glands that signal each other in sequence are usually referred to as an axis, for example, the hypothalamic-pituitary-adrenal axis.
How CNS works…• The multiple activities of the cells, tissues, and organs of the body are coordinated by the interplay of several types of chemical messenger systems:• Neurotransmitters are released by axon terminals of neurons into the synaptic junctions and act locally to control nerve cell functions.
Cortical neuron stained with antibody to neurofilament subunit NF-L in green. In red are neuronal stem cells stained with antibody to alpha-internexin. Image created using antibodies from EnCor Biotechnology Inc
• CNS works through • Endocrine system works Neuron through Hormones• Within milliseconds • Seconds to hours or days• Direct, fast • Indirect and far• Muscles, glands, cells • Cells of body• Briefer action generally • Longer action generally
Hormones1. How they works?2. Chemical classification
Word meaning• Get moving or excite• It is the mediator that is released in one part of the body but regulates the activity of cells in other parts of the body.
• Endocrine hormones are released by glands or specialized cells into the circulating blood and influence the function of cells at another location in the body.
• Only the target cells have receptors that bind and recognize that hormone.• For example, thyroid stimulating hormone TSH binds to receptors on cells of thyroid gland, but it does not bind to cells of the ovaries.
• Receptors, like other cellular protein, are constantly synthesized and broken down.• Generally, a target cell has 2,000 to 1,00,000 receptors for a particular hormone.
• If a hormone is present in excess, the number of target-cell receptors may decrease• This effect is known as DOWN REGULATION.• E.G. when certain cells of the testes are exposed to a high concentration of luteinizing hormone (LH) the number of LH receptors decreases.
• Down regulation make the cell LESS SENSITIVE to a hormone.
• In contrast, when a hormone is deficit, the number of receptors may increase.• This phenomenon is know as UP REGULATION.• It makes the target cell more sensitive to a hormone.
Application• Drug RU486 mifepristone used for abortion• It binds the receptors for progesterone and prevents it from exerting its normal effect.• So no preparation of lining of the uterus for implantation.
• Neuroendocrine hormones are secreted by neurons into the circulating blood and influence the function of cells at another location in the body.
• Paracrines are secreted by cells into the extracellular fluid and affect neighbouring cells of a different type.• Autocrines are secreted by cells into the extracellular fluid and affect the function of the same cells that produced them by binding to cell surface receptors.
• One example of local hormone is interleukin 2.• It is released by helper T cells (WBC)• During immune response, IL-2 helps activating other nearby immune cells, a paracrine effect.• But it also act as autocrine by stimulating the same cell.• This action makes more secretion of IL-2 again.• Thus strengthen the immune response.
• Local hormone used to inactivated quickly; circulating hormones may linger in the blood and exert their effects for a few minutes or occasionally for a few hours.• In time, circulating hormones are inactivated by the liver and excreted by kidneys.• In cases of kidney or liver failure, excessive levels of hormones may build up in the blood.
Chemical classes of hormones• This chemical classification is useful functionally because the two classes exert their effect differently.• 1. lipid soluble• 2. water soluble
• Lipid soluble • Water soluble• S T N (station) • A P E (Appe)• Steroid hormone • Amine hormones• Thyroid hormones • Peptide hormones• Nitric oxide gas • Eicosanoid hormones
Steroid hormones• Derived from cholesterol• Each steroid hormone is unique due to presence of different chemical groups attached at various sites on the four rings at the core of its structure.• These small differences allow for a large diversity of function.
Two thyroid hormones• T3 and T4 are synthesized by attaching iodine to the amino acid tyrosine.• The benzene ring of tyrosine plus the attached iodine make T3 and T4 very lipid soluble.
Nitric oxide• It is both, hormone and neurotransmitter.• Its synthesis is catalyzed by the enzyme nitric oxide synthesis.
Amine hormones• It is synthesized by decarboxylating and otherwise modifying certain amino acids.• They are called amines because they retain an amino acid group (-NH3+).• Epinephrine, norepinephrine, dopamine – synthesized by modifying tyrosine• Histamine is synthesized by histidine• Serotonin and melatonin are derived from tryptophan
Peptide hormones• They are amino acid polymers• Smaller peptide hormones consist of chains of 3 to 49 amino acid• Large protein hormones include 50 to 200 amino acids• EG: Peptide - anti diuretic hormones, oxytocinProtein – growth hormone and insulin
Eicosanoid (i-ko-sa-noid) Hormone• Eicos – twenty and oid – resembling• They derived from arachidonic acid, a 20- carbon fatty acid• EG: Prostaglandins and leukotriene
In short,• Lipid soluble – STN – Steroid = cholesterol – T = thyroid – N = nitric oxide gas• Water soluble – APE – Amine group = -NH3+ - histamine, serotonin – Peptide /Protein = small and large amino acid chain – oxytocin and GH, Insulin – Eicosanoid = 20 carbon fatty acid - Prostaglandins
Hormone transport• Most water soluble hormones circulate in the watery blood plasma in a ‘free’ form (not attached to any molecules).• But most lipid soluble hormone are bound to transport protein.• The transport protein are synthesis by liver and have major three functions:
1. They make lipid soluble hormones temporarily water soluble, thus increasing their solubility in blood2. They retard passage of small hormone molecule through the filtering mechanism in the kidneys, thus slowing the rate of hormone loss in urine3. They provide a ready reserve of hormone, already present in blood streame.
• 0.1 to 10% molecules of lipid soluble hormone are not bound to transport protein. This free fraction diffuses our of capillaries, binds to receptors and triggers responses.• As free hormone molecules leave the blood and bind the receptors, transport protein release new one to replenish the free fraction.
Check point• What is difference between down regulation and up regulation?• Identify the chemical classes of hormones and give an example of each.• How are hormones transported in the blood?
Mechanism of hormone action Two mechanism of hormone action
• Response to a hormone depends on both the hormone and the target cell.• Various target cells respond differently to the same hormone.• Insulin, stimulates synthesis of glycogen in liver cells and synthesis of triglyceride in adipose cells.
• The response of hormone is not always the synthesis of new molecules.• Other effects like,• Changing permeability of plasma membrane• Stimulating transport of a substance into or out of target cells• Alerting the rate of specific metabolic activities• Causing contraction of smooth muscle or cardiac muscles
• These varied effects are possible because a single hormone can set in motion several different cellular responses.• Hormone must announce its arrival to a target cell by binding to its receptors.• The receptors of lipid soluble hormones are located inside target cells.• The receptors of water soluble hormones are part of plasma membrane of target cells.
1. Free lipid solublehormone moleculesdiffuse throughinterstitial fluid,and through lipidbilayer of plasmamembrane intocell.
2. If the cell is targetcell, the hormonebinds with receptorswithin cytosol ornucleus.The activatedreceptor-hormonecomplex then altersgene expression: itturns specific genesof the nuclear DNAon or off.
3. As the DNAtranscribed, newmessengerRNA, mRNAforms, leaves thenucleus, and enterscytosol.It directs synthesisof newprotein, often anenzyme, on theribosomes.
4. The new proteinsalter the cell’sactivity and causethe responsestypical of thathormone.
1. A water solublehormone diffuses fromblood throughinterstitial fluid andthen binds to itsreceptors.The hormone receptorcomplex activatesmembrane proteincalled a G Protein. ThisG protein activatesadenylate cyclase.
2 adenylate cyclaseconverts ATP into cyclicAMP. Because theenzyme’s active site ison the inner surface ofthe plasma membrane,this reaction occurs inthe cytosol of the cell.
3 cyclic AMP, the secondmessenger, activate oneor more proteinkinases, which may befree in the cytosol orbound to plasmamembrane.A protein kinase is anenzyme thatphosphorylates othercellular proteins. Thedonor of phosphate groupis ATP which is now
4 active protein kinasephosphorylate one ofmore cellular proteins.Phosphorylationactivates some ofthese protein andinactivatesothers, rather liketurning switch off oron.
5 Phosphorylated protein in turncause reactions that producephysiological responses. Differentprotein kinases exist withindifferent target cells and withindifferent organelles of the sametarget cell.Thus one protein might triggerglycogen synthesis, a second mightcause the break down oftriglyceride, a third may promoteprotein synthesis, and so forth.
As noted in4, phosphorylation by aprotein kinase can alsoinhibit certain proteins.For example, some ofthe kinases unleashedwhen epinephrinebinds to liver cellsinactive an enzymeneeded for glycogensynthesis.
• 6 After a brief period, an enzyme called phosphodiesterase inactivates cAMP. Thus, the cells response is turned off unless new hormone molecules continue to bind to their receptors in the plasma
Free lipid soluble hormone Water soluble hormone molecule molecule itself as first messenger On exterior surface of plasma mem.Activated receptor-hormone hormone receptor complex complex Activation of G Protein and Adenylate cyclase New DNA transcribed (mRNA) Activation of protein kinase phosphorylation New protein Various hormonal actions Final Hormonal response Inactivation of cAMP
• Besides cAMP, other second messengers are calcium ions Ca+2, cGMP (cyclic guanosine monophosphate), inositol trisphosphate (IP3) and diacyglycerol (DAG).• A given hormone may use different second messengers in different target cells.
• Hormones that binds to plasma membrane receptors can induce their effects at very low concentration because they initiate a cascade or chain reaction, each stop of which multiplies of amplifies the initial effect.• EG: the binding of a single molecule of epinephrine to its receptor on a liver cell may activate a hundred or so G proteins, each of which activates an adenylate cyclase molecule.
• If each adenylate cyclase produces even 1000 cAMp then 1,00,000 of these second messengers will be liberated inside the cell.• Each cAMP may activate a protein kinase, which in turn can act on hundreds or thousands of substrate molecules.
Second messenger system• Hormone receptor complex• G protein• 1. adenylyl cyclase – cAMP system• 2. Gaunyl cyclase – cGMP system• 3. Membrane phopholipase – phospholipid system IP3• 4. calcium – calmodulin system
Classification (Khurana) Amines Proteins, Chemical peptideshormones Steroids A - cAMP Group 1 Mechanism B - cGMP Group 2 C – Ca or IP3 D – Tyrosine kinase
Ca/Insola TyrosinecAMP cGMP te kinase Triphosp Growth ACTH NO hate hormone ADH Oxytocin Insulin Atrial natriuretic factor TSH Acetilecho line
Action of hormone via tyrosine kinase• This mechanism of signal generation from the plasma membrane receptors does not require G Protein intermediaries.• These receptors have an extracellular hormone binding portion, a single trans- membrane portion and an intra-cytoplasmic C terminal portion.
The responsive Influences ness of a target by other cell to a hormone hormones depends on:Abundan ce ofreceptors Concentration of hormone
• A target cell responds more vigorously when the level of a hormone rises or when it has more receptors (up regulation).• In addition, the action of some hormones on target cells require a simultaneous or recent exposure to a second hormone.• In such cases, the second hormone is said to have A PERMISSIVE EFFECT.
• Epinephrine alone only weakly stimulates lipolysis (the break down of triglycerides).• But when small amount of thyroid hormones are present, the same amount of epinephrine stimulates lipolysis much more powerfully.• Sometimes the permissive hormone increases the number of receptor for the other hormone, and sometime it promotes the synthesis of an enzyme required for the expression of other hormones effect.
• When the effect of two hormones acting together is greater or more extensive than effect of each hormone acting alone, the two hormones are said to have SYNERGISTIC effect.• EG: normal development of oocytes in the ovaries requires both FSH from pituitary and estrogen from ovaries.
• When one hormone opposes the action of another hormone, the two hormones are said to have ANTAGONISTIC Effects.• EG: Insulin, which promotes synthesis of glycogen by liver, and glucagon, which stimulates breakdown of glycogen in the liver.
Checkpoint• Which factors determine the responsiveness of target cell to hormone?• What are differences among permissive effects, synergistic effects and antagonistic effects of hormones?
Concentration• Hormones are usually secreted in extreme low concentration – Peptide – 10 -12 to 10 -10 mol/L – Epinephrine – 2 × 10 -10
Half life Half life (The term refers to any period of time in which a quantity falls by half) Protein hormones Amines SteroidsADH < 1 min Epinephrine 10s Aldosterone 30m NorepinephriOxytocin < 1 min 15s Cortisol 90m ne 1,25dihyroxycGH <30 min Thyroxin 5-7d 15 h holecalciferol Triiodothyron 25hydroxychoACTH 15– 25 s 1-3d 15 d ine lecalciferol
Control of hormone secretion Mechanisms of control of hormone secretion
• The release of most of the hormones occurs in short bursts, with little or no secretion between bursts.• When stimulated, an endocrine gland will release its hormone in more frequent bursts, increasing the concentration of hormone in the blood.• In absence of stimulation, the blood level of hormone decreases.
Hormone secretion is regulated by Chemical changes in blood Signals Other from CNS hormones Hormone secretion
Bioassay• Injecting the unknown sample of plasma in experimental animals• Assessing the Quantitative biological effects• Quantitative bioassays involve estimation of the concentration or potency of a substance by measurement of the biological response that it produces. Quantitative bioassays are typically analyzed using the methods of biostatistics.
Immunoassay• Radioimmunoassy (RIA)• Enzyme-linked immunosorbent assay• Studies of antibodies to antigen.
Cytochemical assay• Test is much more sensitive then immunoassay.• Cumbersome and time consuming• Very useful in measuring minute basal levels of hormone secretions.
Dynamic tests• Not as usual normal condition.• Two types• Suppression type – e.g. to know whether a lung cancer is secreting ACTH• Stimulating type – corticotrophs of the pituitary are normally functioning or not.