Test #4 Notes 2

Me taboli c c le arance rate (MCR)

 Defines the quantitative removal of hormone from plasma  The bulk of hormone is cleared by liver and kidneys  Only a small fraction is removed by target tissue  protein and amine hormones bind to receptors and are internalized and degraded  Steroid and thyroid hormones are degraded after hormone-receptor complex binds to nuclear chromatin

MC R of so me h ormo nes Hormone

Half-life

Amines

2-3 min

Thyroid hormones: T4 T3

6.7 days 0.75 days

Polypeptides

4-40 min

Proteins

15-170 min

Steroids

4-120 min

Ho rmone-Re ceptor in te ra ctions  Definition: a protein that binds a ligand with high affinity and low capacity.  A tissue becomes a target for a hormone by expressing a specific receptor for it. Hormones circulate in the blood stream but only cells with receptors for it are targets for its action.

Or ig in al b io assa y syst ems defin ed the endocrine syst em  Remove endocrine gland and observe what happened  Prepare crude extract from gland, inject back into animal and observe what happened  In isolated organ or cell systems, add extract or purified hormonal preparations and measure biological response

Ho rmonal measu rements  Chemical methods  

chromatography spectrophotometery

Ra dioimmu noassa y  Radioactive ligand and unlabeled ligand compete for same antibody. Competition is basis for quantitation  saturate binding sites with radioactively labeled hormone (ligand)  in parallel incubate complex with unknown and determine its concentration by comparison

Cla sse s o f hormo nes    The hormones fall into two general classes based on their solubility in water. The water soluble hormones are the catecholamines (epinephrine and norepinephrine) and peptide/protein hormones. The lipid soluble hormones include thyroid hormone, steroid hormones and Vitamin D3

Typ es of r eceptors  Receptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane.  These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell.

 Receptors for the lipid soluble hormones reside in the nucleus (and sometimes the cytoplasm) of the target cell.  Because these hormones can diffuse through the lipid bilayer of the plasma membrane, their receptors are located on the interior of the target cell

Ho rmones and their recepto rs Hormone

Class of hormone

Location

Amine (epinephrine)

Water-soluble

Cell surface

Amine (thyroid hormone)

Lipid soluble

Intracellular

Peptide/protein

Water soluble

Cell surface

Steroids and Vitamin D

Lipid Soluble

Intracellular

Se cond me ssenger syst ems  Receptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane. These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell

Se cond m esse ngers f or cell- su rface receptors  Second messenger systems include:  Adenylate cyclase which catalyzes the conversion of ATP to cyclic AMP;  Guanylate cyclase which catalyzes the conversion of GMP to cyclic GMP (cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides);  Calcium and calmodulin; phospholipase C which catalyzes phosphoinositide turnover producing inositol phosphates and diacyl glycerol.

Typ es of r eceptors

Se cond m esse nger syst ems  Each of these second messenger systems activates a specific protein kinase enzyme.  These include cyclic nucleotide-dependent protein kinases  Calcium/calmodulin-dependent protein kinase, and protein kinase C which depends on diacyl glycerol binding for activation.  Protein kinase C activity is further increased by calcium which is released by the action of inositol phosphates.

Se cond me ssenger syst ems  The generation of second messengers and activation of specific protein kinases results in changes in the activity of the target cell which characterizes the response that the hormone evokes.  Changes evoked by the actions of second messengers are usually rapid

Si gnal transducti on mechani sms of hor mones Activation of adenylate cyclase

Inhibition of adenylate cyclase

Increased phosphoinositide turnover

Tyrosine kinase activation

β-adrenergic

α2-adrenergic

α1-adgrenergic

Insulin

LH, FSH, TSH, hCG

Opioid

Angiotensin II

Growth factors (PDGF, EGF, FGF, IGF-1

Glucagon

Muscarinic cholinergic – M2

Muscarinic cholinergic – M3

Growth hormone

Vasopressin –V1

Prolactin

Vasopressin- V2 ACTH

Cell s urfa ce r eceptor actio n

G-p rotein c ouple d recepto rs

Adenylate cyclase, cAMP and PKA

Amplification via 2nd messenger

Tr ansme mbrane kin ase -li nked recepto rs  Certain receptors have intrinsic kinase activity.

These include receptors for growth factors, insulin etc.

 Other tyrosine-kinase associated receptor, such as those for Growth Hormone, Prolactin and the cytokines, do not have intrinsic kinase activity, but activate soluble, intracellular kinases such as the Jak kinases.  In addition, a newly described class of receptors have intrinsic serine/threonine kinase activity—this class includes receptors for inhibin, activin, TGFβ, and Mullerian Inhibitory Factor (MIF).

Protei n tyros ine ki nase recepto rs

Re ceptors for l ip id so lu ble hormo nes resid e within t he c ell

 These hormones can diffuse through the lipid bilayer of the plasma membrane, their receptors are located on the interior of the target cell.  Diffuses into the cell and binds to the receptor which undergoes a conformational change. The receptorhormone complex is then binds to specific DNA sequences called response elements.  These DNA sequences are in the regulatory regions of genes.

Re ceptors for l ip id so lu ble h ormo nes resid e with in t he c ell  The receptor-hormone complex binds to the regulatory region of the gene and changes the expression of that gene.  In most cases binding of receptor-hormone complex to the gene stimulating the transcription of messenger RNA.  The messenger RNA travels to the cytoplasm where it is translated into protein. The translated proteins that are produced participate in the response that is evoked by the hormone in the target cell  Responses evoked by lipid soluble hormones are usually SLOW, requiring transcription/translation to evoke physiological responses.

Me chanism of lipid sol uble hormo ne action

Re ceptor control mechanism s  Hormonally induced negative regulation of receptors is referred to as homologous-desensitization  This homeostatic mechanism protects from toxic effects of hormone excess.  Heterologous desensitization occurs when exposure of the cell to one agonist reduces the responsiveness of the cell any other agonist that acts through a different receptor.  This most commonly occurs through receptors that act through the adenylyl cyclase system.

Me chanisms of endocrine dise ase  Endocrine disorders result from hormone deficiency, hormone excess or hormone resistance  Almost without exception, hormone deficiency causes disease  One notable exception is calcitonin deficiency

Me chanism s of endocrine dise ase  Deficiency usually is due to destructive process occurring at gland in which hormone is produced—infection, infarction, physical compression by tumor growth, autoimmune attack Type I Diabetes

Me chanism s of endocrine dise ase  Deficiency can also arise from genetic defects in hormone production—gene deletion or mutation, failure to cleave precursor, specific enzymatic defect (steroid or thyroid hormones) Congenital Adrenal Hyperplasia

Me chanism s of endocrine dise ase  Inactivating mutations of receptors can cause hormone deficiency

Testicular Feminization Syndrome

Me chanism s of endocrine dise ase  Hormone excess usually results in disease  Hormone may be overproduced by gland that normally secretes it, or by a tissue that is not an endocrine organ.  Endocrine gland tumors produce hormone in an unregulated manner. Cushing’s Syndrome

Me chanism s of endocrine dise ase  Exogenous ingestion of hormone is the cause of hormone excess—for example, glucocorticoid excess or anabolic steroid abuse

Me chanism s of endocrine dise ase  Malignant transformation of nonendocrine tissue causes dedifferentiation and ectopic production of hormones  Anti-receptor antibodies stimulate receptor instead of block it, as in the case of the common form of hyperthyroidism. Grave’s Disease

Me chanism s of endocrine dise ase  Alterations in receptor number and function result in endocrine disorders  Most commonly, an irregular increase in the level of a specific hormone will cause a decrease in available receptors Type II diabetes

Various types of abnormal secretion of a target organ hormone (TOH), which is normally regulated by a tropic hormone (TH) from the anterior pituitary. Bold and broken lines depict greater and less than normal rates of secretion, respectively. Crosshatching indicates the location of the defect. Simulation and inhibition are indicated by (+) and (-), respectively.

Hy pot hal am us and P itu it ar y

Hyp oth ala mu s and Pitu itary  The hypothalamus-pituitary unit is the most dominant portion of the entire endocrine system.  The output of the hypothalamus-pituitary unit regulates the function of the thyroid, adrenal and reproductive glands and also controls somatic growth, lactation, milk secretion and water metabolism.

Hypothal amus and pi tui tary gl and

Hypothal amus and pi tui tary gl and

Hypothala mu s and Pit uitary  Pituitary function depends on the hypothalamus and the anatomical organization of the hypothalamus-pituitary unit reflects this relationship.  The pituitary gland lies in a pocket of bone at the base of the brain, just below the hypothalamus to which it is connected by a stalk containing nerve fibers and blood vessels. The pituitary is composed to two lobes-anterior and posterior

Po st erio r Pituita ry: neuro hyp ophysis  Posterior pituitary: an outgrowth of the hypothalamus composed of neural tissue.  Hypothalamic neurons pass through the neural stalk and end in the posterior pituitary.  The upper portion of the neural stalk extends into the hypothalamus and is called the median eminence.

Hypothal amus and posteri or pi tui tary Midsagital view illustrates that magnocellular neurons paraventricular and supraoptic nuclei secrete oxytocin and vasopressin directly into capillaries in the posterior lobe

An terio r pituit ary: adenohyp ophysis  Anterior pituitary: connected to the hypothalamus by the superior hypophyseal artery.  The antererior pituitary is an amalgam of hormone producing glandular cells.  The anterior pituitary produces six peptide hormones:

prolactin, (PRL) growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH).

Hypothal amu s and anteri or pi tui tary neurosecretory

TSH LH FSH

cells secrete releasing factors into capillaries of the pituitary portal system at the median eminence which are then transported to the anterior pituitary gland to regulate the secretion of pituitary hormones.

Anatomi cal and functi onal or ga niz ati on

neocortex Reticular activating substance Sleep/ wake

Thalamus

Limbic system

pain

Emotion, fright, rage, smell

Heat regulation (temperature)

Water balance (blood volume, intake--thirst, output—urine volume)

Energy regulation (hunger, BMI)

Regula tion of Hyp othalam us

Optical system vision

Autonomic regulation (blood pressure etc)

Metabolic rate, stress response, growth, reproduction, lactation)

posterior pituitary hormones

Anterior pituitary hormones

Hypot halamus/ Pi tu itary Axis Posterior Pituitary

Hyp othalamic releas ing factor s fo r anter ior pit uit ary hormo nes  Travel to adenohypophysis via hypophysealportal circulation  Travel to specific cells in anterior pituitary to stimulate synthesis and secretion of trophic hormones

Hypothal ami c rel easi ng hormones Hypothalamic releasing hormone Corticotropin releasing hormone (CRH) Thyrotropin releasing hormone (TRH) Growth hormone releasing hormone (GHRH) Somatostatin

Gonadotropin releasing hormone (GnRH) a.k.a LHRH Prolactin releasing hormone (PRH) Prolactin inhibiting hormone (dopamine)

Effect on pituitary

Stimulates ACTH secretion 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

Characteri sti cs of hypot halam ic rel easi ng horm ones Secretion in pulses Act on specific membrane receptor Transduce signals via second messengers Stimulate release of stored pituitary hormones Stimulate synthesis of pituitary hormones Stimulates hyperplasia and hypertophy of target cells  Regulates its own receptor      

Hypot hal am us and anteri or pi tui tary

Anterior pituitary  Anterior pituitary: connected to the hypothalamus by hypothalmoanterior pituitary portal vessels.  The anterior pituitary produces six peptide hormones:     

prolactin, growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH).

Anteri or pi tui tary cel ls and hormones Cell type

Pituitary Product population

Target

Corticotroph

15-20%

Thyrotroph Gonadotroph

3-5% 10-15%

Adrenal gland ACTH β-lipotropin Adipocytes Melanocytes TSH Thyroid gland LH, FSH Gonads

Somatotroph

40-50%

GH

Lactotroph

10-15%

PRL

All tissues, liver Breasts gonads

An terio r pituit ary hormones