ENDOCRINE SYSTEM 1

ENDOCRINE SYSTEM Endocrine system Composed of glands “Ductless glands” Secrete chemical signals into the bloodstream (Exocrine glands secrete substances through ducts to surfaces) Secretory products are hormones

HORMONES Hormones Chemical signal (“ligand”) Produced in minute amounts by a collection of cells Secreted into the interstitial spaces Enters the circulatory system Transported throughout the body Influences the activity of specific tissues “Target tissues”

REGULATION Endocrine and nervous systems both regulate the activities of structures within the body Accomplished in different ways Hormones are amplitude-modulated signals Signals consist mainly of increases or decreases in the concentration of hormones in body fluids Response produced within several seconds to hours Action potentials are frequency-modulated signals Action potentials vary in frequency but not in amplitude Response produced within milliseconds

REGULATION Nervous and endocrine systems are intimately related The two systems cannot be completely separated either anatomically or functionally e.g., Some neurons secrete neurohormones into the circulatory system Function like hormones e.g., Some neurons directly innervate endocrine glands and influence their secretory activity e.g., Some hormones secreted by endocrine glands affect the nervous system and influence its activity

CHEMICAL SIGNALS Intercellular chemical signals allow cells to communicate with each other e.g., Neurotransmitters, neuromodulators, and hormones There are various types of intercellular signals Autocrine chemical signals Paracrine chemical signals Pheromones

CHEMICAL SIGNALS Autocrine chemical signals Released by cells and have an effect on similar cells e.g., Prostaglandins are released by smooth muscle cells and platelets in response to inflammation Causes aggregation of platelets and relaxation of blood vessel smooth muscle

CHEMICAL SIGNALS Paracrine chemical signals Released by cells and affect other cell types locally without being transported in the blood e.g., The peptide somatostatin is released by cells in the pancreas and functions locally to inhibit the secretion of insulin from other cells of the pancreas

CHEMICAL SIGNALS Pheromones Secreted into the environment and modify the behavior and physiology of other individuals e.g., Pheromones released in urine of cats and dogs signal fertility e.g., Pheromones released by women influence the menstrual cycles of other women

CHEMICAL SIGNALS Many intercellular chemical signals consistently Intercellular signals Many consistently fit one specific definition Many do not consistently fit one specific definition e.g., Norepinephrine functions both as a neurotransmitter and a neurohormone

HORMONE STRUCTURE Three main classes of hormones Polymers of amino acids Proteins or polypeptides Glycoprotein hormones contain carbohydrate components Derivatives of single amino acids Lipids Steroids or derivatives of fatty acids

SECRETION Most hormones are not secreted at a constant rate Secretion increases and decreases dramatically over time Secretion rate generally controlled by negative feedback Body activity regulated is maintained within normal range Homeostasis is maintained Secretion is sometimes regulated by positive feedback Less frequent e.g., components of the female reproductive system Estrogen stimulates LH secretion LH stimulates estrogen secretion

SECRETION Three major patterns of regulation Changes in the extracellular concentration of a non-hormone molecule can affect an endocrine gland Neural control of the endocrine gland Control of hormone secretion by another hormone or neurohormone Regulation of hormone secretion often involves more than one of these mechanisms

SECRETION Changes in the extracellular concentration of a non-hormone molecule can affect an endocrine gland e.g., Blood glucose levels affect insulin secretion from the pancreas Insulin increases glucose movement into cells Insulin secretion decreases

SECRETION Neural control of the endocrine gland Neurons synapse with hormone-producing cells Neurotransmitter release stimulates or inhibits hormone release e.g., Stress or exercise stimulates the adrenal gland to secrete epinephrine and norepinephrine

SECRETION Control of hormone secretion by another hormone or neurohormone e.g., Thyroid-releasing hormone (TRH) from the hypothalamus stimulates the secretion of thyroid-stimulating hormone (TSH) from the anterior pituitary gland TSH stimulates the secretion of thyroid hormones (T3 & T4) etc.

SECRETION Some hormones are in the circulatory system at relatively constant levels e.g., Thyroid hormones Levels of some hormones change suddenly in response to certain stimuli e.g., Epinephrine is released in response to stress or exercise Levels of some hormones change in relatively constant cycles e.g., Reproductive hormones cycle in women during their reproductive years

SECRETION Some hormones are in the circulatory system at relatively constant levels e.g., Thyroid hormones

SECRETION Levels of some hormones change suddenly in response to certain stimuli e.g., Epinephrine is released in response to stress or exercise

SECRETION Levels of some hormones change in relatively constant cycles e.g., Reproductive hormones cycle in women during their reproductive years

HORMONE TRANSPORT Hormones are dissolved in blood plasma Transported in two fashions Free form Bound to plasma proteins

HORMONE TRANSPORT Free hormones diffuse readily into interstitial spaces Concentration of hormone in the blood affects the amount of hormone diffusing into interstitial spaces

HORMONE TRANSPORT Many hormones bind only to certain types of plasma proteins e.g., The type of plasma protein binding to thyroid hormones differs from the type of plasma protein binding to testosterone

HORMONE TRANSPORT Hormones that bind to plasma proteins do so reversibly H + BP  HBP This equilibrium is important Only free hormone can diffuse into the interstitial space Hormones bound to plasma proteins tend to remain at a relatively constant level in the blood for long periods of time Decrease in plasma protein concentration reduces half-life of hormone

HORMONE TRANSPORT A decrease in plasma protein concentration reduces the half-life of hormone Eliminated in either the kidneys of the liver

HORMONE TRANSPORT The circulatory system quickly distributes hormones throughout the body Diffuse through capillary endothelium Rate varies between hormones Lipid-soluble hormones readily diffuse through the walls of all capillaries Water-soluble hormones pass through pores (“fenestrae”) in the capillary endothelium Capillary endothelia of organs regulated by protein hormones have large pores Endocrine glands secreting these hormones also have large pores

METABOLISM & EXCRETION Hormone destruction and elimination limit the time in which they are active Water-soluble hormones have relatively short half-lives Rapidly degraded by enzymes Present in circulatory system or organs Normally have concentrations that increase and decrease rapidly Generally regulate activities that have a rapid onset and a short duration

METABOLISM & EXCRETION Hormone destruction and elimination limit the time in which they are active Lipid-soluble hormones have relatively long half-lives Commonly circulate in the blood bound to plasma proteins Reduces rate of elimination Reduces rate at which they diffuse through capillary endothelium Normally maintained at relatively constant levels

METABOLISM & EXCRETION Four main modes of hormone removal from the blood Excretion Metabolism Active transport Conjugation

METABOLISM & EXCRETION Four main modes of hormone removal from the blood Excretion Kidneys excrete hormones into the urine Liver excretes hormones into the bile

METABOLISM & EXCRETION Four main modes of hormone removal from the blood Metabolism Hormones metabolized or chemically modified Enzymes in blood or tissues e.g., Liver, kidneys, lungs, etc. End products may be excreted in urine or bile End products may be taken up by cells e.g., Epinephrine is modified, then excreted e.g., Protein hormones are broken down into amino acids Amino acids are then taken up by cells

METABOLISM & EXCRETION Four main modes of hormone removal from the blood Active transport Actively transported into cells Hormones are recycled e.g., Epinephrine and norepinephrine are actively transported into cells These hormones can be secreted again

METABOLISM & EXCRETION Four main modes of hormone removal from the blood Conjugation Attachment of water-soluble molecules to hormones Typically sulfate or glucuronic acid Increases rate of excretion by kidneys or liver

INTERACTION WITH TARGET TISSUES Intercellular chemical signals “Ligands” Bind to proteins and change their functions Various classes Hormones Neurotransmitters Chemical mediators of inflammation

INTERACTION WITH TARGET TISSUES Ligands bind to proteins at their binding site Receptor site if protein is a receptor Lock-and-key fit “Specificity” e.g., Insulin binds to insulin receptors e.g., Insulin does not bind to growth hormone receptors Multiple types of receptors exist for some hormones e.g., There are multiple types of epinephrine receptors

INTERACTION WITH TARGET TISSUES Hormones are distributed throughout the body by the circulatory system Target cells respond to a given hormone Possess receptors to which the hormone binds Cells lacking receptors do not respond

INTERACTION WITH TARGET TISSUES Drugs with structures similar to a particular chemical signal may compete with that molecule for their receptor sites Binding some drugs activates the receptors Binding of some drugs inhibits the receptor Blocks binding by the hormone e.g., RU486 binds to progesterone receptors Prevents binding by progesterone Prevents the maintenance of pregnancy

INTERACTION WITH TARGET TISSUES Response to a given concentration of chemical signal Constant in some cases Variable in some cases Two common reasons Fatigue in the target cells after prolonged stimulation Number of receptors can decrease after exposure to certain chemical signals “Down-regulation” Two mechanisms Decreased rate of receptor synthesis Increased rate of receptor degradation

INTERACTION WITH TARGET TISSUES Neurons of the hypothalamus release GnRH Causes secretion of FSH and LH from the anterior pituitary Exposure to GnRH causes a reduction in the number of GnRH receptors in cells of the anterior pituitary Dramatic decrease several hours after exposure Pituitary becomes less sensitive to GnRH Normal response of pituitary depends on periodic (not constant) exposure to GnRH

INTERACTION WITH TARGET TISSUES Tissues exhibiting down-regulation of receptors generally respond to short-term increases in hormone concentrations Tissues responding to relatively constant levels of hormones normally do not exhibit down-regulation

INTERACTION WITH TARGET TISSUES Periodic increases in sensitivity to certain hormones can also occur “Up-regulation” Results from an increase in the rate of receptor molecule synthesis e.g., Increased number of LH receptors in the ovary during each menstrual cycle FSH from pituitary increases synthesis of LH receptor

CLASSES OF RECEPTORS Two main categories of chemical signals (And two main categories of receptors) Those binding to membrane-bound receptors Those binding to intracellular receptors

CLASSES OF RECEPTORS Some chemical signals cannot pass through the plasma membrane Large molecules and water-soluble molecules Bind to membrane-bound receptors Transmembrane receptor proteins Receptor site exposed on outer surface Binding of signal to receptor initiates a response inside the cell

CLASSES OF RECEPTORS Some chemical signals readily pass through the plasma membrane Small and lipid soluble molecules Bind to intracellular receptors Hormone-receptor complex may bind to DNA Alters gene expression Hormone-receptor complex may bind to enzymes

CLASSES OF RECEPTORS Signals binding to membrane-bound receptors Protein hormones Glycoprotein hormones Polypeptides Some smaller molecules Epinephrine Norepinephrine etc. Signals binding to intracellular receptors Thyroid hormones Steroid hormones Testosterone Estrogen Progesterone Aldosterone Cortisol etc.

CLASSES OF RECEPTORS Membrane-bound receptors Integral membrane proteins Hormone-receptor binding is reversible Binding stimulates the intracellular portion of receptor to initiate a response Three major mechanisms of responses Altered membrane permeability Altered activity of G proteins Altered activity of intracellular enzymes

CLASSES OF RECEPTORS Receptors altering membrane permeability Some receptors comprise part of an ion channel Ligand-gated ion channels Binding alters shape of channel Causes channel to either open or close Results in a change in the membrane’s permeability to the specific ions passing through the channel

CLASSES OF RECEPTORS Receptors activating G proteins G proteins Bind to receptors at inner surface of plasma membrane Inactive state binds to GDP

CLASSES OF RECEPTORS Receptors activating G proteins Receptor changes shape upon binding to hormone GTP replaces GDP on G protein Alpha subunit separates from other subunits Alpha subunit can influence ion channels or form intracellular mediators (“second messengers”)

CLASSES OF RECEPTORS Receptors activating G proteins Hormone separates from the receptor G proteins are no longer activated Alpha subunits are inactivated as GTP  GDP

CLASSES OF RECEPTORS Receptors activating G proteins Some G proteins activate Ca2+ channels Ca2+ enters the cell Can function as an intracellular mediator Enters or is synthesized inside the cell Regulates enzyme activities inside the cell

CLASSES OF RECEPTORS Receptors activating G proteins Ca2+ can combine with calmodulin molecules Calcium-calmodulin complexes activate enzymes Thee enzymes cause contraction of smooth muscle

CLASSES OF RECEPTORS Receptors activating G proteins Some G proteins alter enzyme activity Activated alpha subunits can activate the enzyme adenylate cyclase ATP  cAMP cAMP binds to kinases Activated kinases phosphorylate other enzymes Activity of these enzymes is altered Either increased or decreased cAMP is inactivated (cAMP AMP) by the enzyme phosphodiesterase

CLASSES OF RECEPTORS Cyclic AMP acts as an intracellular mediator in many cell types Enzymes activated are different Response of each cell type is different e.g., Glucagon  release of glucose from liver cells e.g., LH  ovulation

CLASSES OF RECEPTORS The combination of chemical signals with their receptors doesn’t always result in increased cAMP synthesis Sometimes cAMP synthesis is inhibited by G proteins There are other common intracellular mediators e.g., Diacyl glycerol (DAG) e.g., Inositol triphosphate (IP3)

CLASSES OF RECEPTORS Epinephrine binds to certain receptors in some types of smooth muscle Binding activates a G protein Phospholipase C is activated Phosphoinositol diphosphate (PIP2)  DAG + IP3 DAG activates enzymes that synthesize prostaglandins Smooth muscle contraction is increased IP3 releases Ca2+ from the E.R. Ca2+ enters the cytoplasm and increases smooth muscle contraction

CLASSES OF RECEPTORS Some receptors directly alter the activity of intracellular enzymes Intracellular enzymes controlled by the membrane-bound receptors May be part of the receptor May be separate molecules

CLASSES OF RECEPTORS Some receptors directly alter the activity of intracellular enzymes Effects of altered enzyme activity Increased or decreased synthesis of intracellular mediator molecules Phosphorylation of intracellular proteins Effects of intracellular mediators or phosphorylated proteins Activation of processes that produce the response of cells to the chemical signals

CLASSES OF RECEPTORS Some receptors directly alter the activity of intracellular enzymes Intracellular mediator molecules act as chemical signals Move from enzymes that produced them into the cytoplasm Activate processes that produce the response of the cell

CLASSES OF RECEPTORS Some receptors directly alter the activity of intracellular enzymes Cyclic guanine monophosphate cGMP Intracellular mediator molecule Synthesized in response to chemical signal binding with a membrane-bound receptor Produced by the enzyme guanylate cyclase GTP  cGMP

CLASSES OF RECEPTORS Some receptors directly alter the activity of intracellular enzymes Cyclic guanine monophosphate Combine with and activate specific cytoplasmic enzymes Activated enzymes produce the response of the cell to the chemical signal

CLASSES OF RECEPTORS Some receptors directly alter the activity of intracellular enzymes e.g., ANH binds to receptor in kidney cell membrane Increased cGMP synthesis Influences action of enzymes Stimulates Na+ and H2O excretion Phosphodiesterase breaks down cGMP cGMP  GMP Signal quickly disappears when hormone disappears

CLASSES OF RECEPTORS Some receptors directly alter the activity of intracellular enzymes Cytoplasmic portion of receptor acts as a phosphorylase enzyme Phosphorylates several specific proteins Some are part of the membrane-bound receptor Others are cytoplasmic proteins Phosphorylated proteins influence activity of other cytoplasmic enzymes

CLASSES OF RECEPTORS Many hormones stimulate the synthesis of an intracellular mediator molecule Often produce rapid responses Mediator influences already-existing enzymes Causes a cascade event Few mediator molecules activate several enzymes Each activated enzyme activates several other enzymes Final response is produced

CLASSES OF RECEPTORS Intracellular receptors Present in either the cell’s cytoplasm or nucleus Lipid-soluble chemical signals Cross the plasma membrane Bind to intracellular receptors Hormone-receptor complex has one of two effects Alter the activity of cellular enzymes Bind to DNA and alter the expression of genes

CLASSES OF RECEPTORS Receptors binding to DNA Activate certain specific genes Transcription of these genes increases Specific proteins are produced e.g., Testosterone and estrogen stimulate the production of the proteins responsible for secondary sexual characteristics e.g., Aldosterone stimulates kidney cells to synthesize proteins increasing the rate of Na+ and K+ transport Results in increased reabsorption of Na+ and increased K+ secretion

CLASSES OF RECEPTORS

CLASSES OF RECEPTORS Cells synthesizing proteins in response to hormonal stimuli normally have a latent period of several hours Hormones bind, responses are observed