Chapter 17. Lecture and Animation Outline

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Chapter 17 Functional Organization of the Endocrine System 17-2

17.1 Principles of Chemical Communication Classes of Chemical Messengers Autocrine chemical messengers: released by cells and have a local effect on same cell type from which chemical signals released; e.g., prostaglandin Paracrine chemical messengers: released by cells and affect other cell types locally without being transported in blood; e.g., somatostatin Neurotransmitter: produced by neurons and secreted into extracellular spaces by presynaptic nerve terminals; travels short distances; influences postsynaptic cells; e.g., acetylcholine. Endocrine chemical messengers: type of intercellular signal. Produced by cells of endocrine glands, enter circulatory system, and affect distant cells; e.g., estrogen 17-3

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. TABLE 17.1 Classes of Chemical Messengers Chemical Messenger Description Example Autocrine Secreted by cells in a local area; influences the activity of the same cell from which it was secreted Eicosanoids (prostaglandins, thromboxanes, prostacyclins, leukotrienes) Chemical messenger Autocrine Paracrine Produced by a wide variety of tissues and secreted into extracellular fluid; has a localized effect on other tissues Somatostatin, histamine, eicosanoids Chemical messenger Paracrine Neurotransmitter Produced by neurons; secreted into a synaptic cleft by presynaptic nerve terminals; travels short distances; influences postsynaptic cells Acetylcholine, epinephrine Neuron Neurotransmitter Endocrine Secreted into the blood by specialized cells; travels some distance to target tissues; results in coordinated regulation of cell function Thyroid hormones, growth hormone, insulin, epinephrine, estrogen, progesterone, testosterone, prostaglandins Hormone Endocrine 17-4

Characteristics of the Endocrine System Glands that secrete chemical messengers (hormones) into circulatory system Hormone characteristics Produced in small quantities Secreted into intercellular space Transported some distance in circulatory system Acts on target tissues elsewhere in body Regulate activities of body structures Ligands: more general term for chemical signals 17-5

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Hypothalamus Pituitary Pineal gland Thyroid Thymus Parathyroids (posterior part of thyroid) Adrenals Ovaries (female) Pancreas (islets) Testes (male) 17-6

Comparison of Nervous and Endocrine Systems Similarities 1. Both systems associated with the brain Hypothalamus Epithalamus 2. May use same chemical messenger as neurotransmitter and hormone. Epinephrine 3. Two systems are cooperative Nervous system secretes neuroendocrine peptides, or neurohormones, into circulatory system Some parts of endocrine system innervated directly by nervous system 17-7

(mv) Hormone concentration in blood Comparison of Nervous and Differences 1. Mode of transport Axon Blood 2. Speed of response Endocrine Systems Nervous instant/milliseconds Endocrine delayed/seconds 3. Duration of response Nervous milliseconds/seconds Endocrine minutes/days Amplitude vs. frequency Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Weak signal Strong signal Time (minutes to hours) Stronger signal Amplitude-modulated system. The concentration of the hormone determines the strength of the signal and the magnitude of the response. For most hormones, a small concentration of a hormone is a weak signal and produces a small response, whereas a larger concentration is a stronger signal and results in a greater response. 0 85 Weak signal Strong signal Time (msec. to seconds) Stronger signal Frequency-modulated system. The strength of the signal depends on the frequency, not the size, of the action potentials. All action potentials are the same size in a given tissue. A low frequency of action potentials is a weak stimulus, and a higher frequency is a stronger stimulus. 17-8

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17.2 Hormones General Characteristics of Hormones 1. Stability Half-life: The length of time it takes for half a dose of substance to be eliminated from circulatory system Long half-life: regulate activities that remain at a constant rate through time. Usually lipid soluble and travel in plasma attached to proteins Short half-life: water-soluble hormones as proteins, epinephrine, norepinephrine. Have a rapid onset and short duration 2. Communication Interaction with target cell 3. Distribution Hormones dissolve in blood plasma and are transported in unbound or are reversibly bound to plasma proteins. Hormones are distributed quickly because they circulate in the blood. 17-10

Protein Bound Transport Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Endocrine cell Water-soluble hormones Water-soluble hormone target cell Water-soluble hormones Membrane-bound receptor Circulating blood Binding protein Lipid-soluble hormones Capillary Bound hormone Free lipid-soluble hormone Endocrine cell Lipid-soluble hormones Nuclear receptor Lipid-soluble hormone target cell 17-11

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. TABLE 17.2 Chemical Nature of Hormones Chemical Nature Examples Structures Lipid-Soluble Hormones Steroids (all cholesterolbased) Testosterone, aldosterone HO Aldosterone O H C CH 2 OH C O CH 3 CH 3 OH O O Testosterone Amino acid derivative (only one example of lipid-soluble) Thyroid hormone (thyroxine) HO I O I H H C C COOH H NH I I 2 Tetraiodothyronine or thyroxine (T 4 ) Fatty acid derivatives Prostaglandins Fatty acid OH derivative (for med from a fatty acid) OH OH Prostaglandin F 2 (PGF 2 ) COOH 17-12

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. TABLE 17.2 Chemical Nature of Hormones Chemical Nature Examples Structures Water-Soluble Hormones Proteins Thyroid-stimulating hormone, growth hormone N Peptides NH 2 O Thyroid-stimulating Hormone (a glycoprotein) Growth hormone N NH HN O O Insulin, thyrotropin-releasing hormone S S NH O Thyrotropin-releasing hormone Gly-Ile-Val-Glu-Gln-Cys-Cys-Thr-Ser-Ile-Cys-Ser-Leu-Tyr-Gln-Leu-Glu-Asn-Tyr Cys-Asn S S S S A chain B chain Insulin Phe-Val-Asn-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe-Phe-Tyr-Thr-Pro-Lys-Thr 17-13

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. TABLE 17.2 Chemical Nature of Hormones Chemical Nature Examples Structures Amino acid derivatives Epinephrine Epinephrine HO HO CH OH CH 2 NH CH 3 17-14

Hormone levels in blood Hormone levels in blood Hormone levels in blood Patterns of Hormone Secretion Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chronic hormone regulation. Maintenance of relatively constant concentration of hormone. Thyroid hormone. (a) Time (days or weeks) Chronic hormone secretion. A relatively stable concentration of hormone is maintained in the circulating blood over a relatively long period. This pattern is exemplified by the thyroid hormones. Acute hormone regulation. Epinephrine in response to stress. Stimulus Stimulus Stimulus Time (minutes or hours) (b) Acute hormone secretion. A hormone rapidly increases in the blood for a short time in response to a specific stimulus for example, Insulin (the blood sugar regulating hormone) secretion following a meal. Note that the size of the stimulus arrow represents its strength. A smaller stimulus does not activate as much hormone secretion as a larger stimulus. Episodic (Cyclic) hormone regulation. Female reproductive hormones. Stimulus Stimulus Stimulus Time (days) (c) Episodic hormone secretion. A hormone is stimulated so that it increases and decreases in the blood at a relatively consistent time and to roughly the same a mount. Examples are the reproductive hormones regulating menstruation. 17-15

17.3 Control of Hormone Secretion Most hormones controlled by negative feedback systems Most hormones are not secreted at constant rate, but their secretion is regulated by three different methods 1. The action of a substance other than a hormone on an endocrine gland. 2. Neural control of endocrine gland. 3. Control of secretory activity of one endocrine gland by hormone or neurohormone secreted by another endocrine gland 17-16

Control by Humoral Stimuli Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. PTH Ca 2+ Endocrine cell when blood Ca 2+ is too low Osteoclast No PTH secretion Ca 2+ Endocrine cell when blood Ca 2+ is too high 17-17

Control by Neural Stimuli Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Neuron 1 An action potential (AP) in a neuron innervating an endocrine cell stimulates secretion of a stimulatory neurotransmitter. 2 The endocrine cell secretes its hormone into the blood where it will travel to its target. AP 3 An AP in the neuron stimulates secretion of an inhibitory neurotransmitter. 4 The endocrine cell is inhibited and does not secrete its hormone. 1 3 Stimulatory neurotransmitter Inhibitory neurotransmitter Endocrine cell 4 Hormone not secreted 2 Hormone secreted Capillary 17-18

Control by Hormonal Stimuli Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Stimulatory Hypothalamus Inhibitory Inhibiting hormone 5 1 Releasing hormone Anterior pituitary Posterior pituitary Tropic hormone 2 Negative feedback 4 Target 3 Target endocrine cell Hormone 1 2 3 4 5 Neurons in the hypothalamus release stimulatory hormones, called releasing hormones. Releasing hormones travel in the blood to the anterior pituitary gland. Releasing hormones stimulate the release of tropic hormones from the anterior pituitary, which travel in the blood to their target endocrine cell. The target endocrine cell secretes its hormone into the blood, where it travels to its target and produces a response. The hormone from the target endocrine cell also inhibits the hypothalamus and anterior pituitary from secreting the releasing hormone and the tropic hormone. This is negative feedback. In some instances, the hypothalamus can also secrete inhibiting hormones, which prevent the secretion of anterior pituitary tropic hormones. 17-19

Negative Feedback Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 Anterior pituitary Tropic hormone Negative feedback 3 Target 2 Target Endocrine cell Hormone (a) Negative feedback by hormones 1 The anterior pituitary gland secretes a tropic hormone, which travels in the blood to the target endocrine cell. 2 The hormone from the target endocrine cell travels to its target. 3 The hormone from the target endocrine cell also has a negative-feedback effect on the anterior pituitary and hypothalamus and decreases secretion of the tropic hormone. 17-20

Positive Feedback Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 Anterior pituitary Tropic hormone Positive feedback 3 Target 2 Target Endocrine cell Hormone (b) Positive feedback by hormones 1 2 The anterior pituitary gland secretes a tropic hormone, which travels in the blood to the target endocrine cell. The hormone from the target endocrine cell travels to its target. 3 The hormone from the target endocrine cell also has a positive-feedback effect on the anterior pituitary and increases secretion of the tropic hormone. 17-21

17.4 Hormone Receptors and Mechanisms of Action Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Hormone Membrane-bound receptors Nuclear receptors Receptors alter the activity of G proteins. Receptors alter the activity of intracellular enzymes. Activate genes Open or close ion channels and activate existing enzymes Activate existing enzymes Synthesize new proteins or enzymes Cell responds 17-22

Target Tissue Specificity and Response Circulating blood Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Capillary Hormone 1 bound to its receptor Hormone 1 Hormone 1 receptor Target cell for hormone 1 Hormone 2 Hormone 2 cannot bind to this receptor Portion of molecule where hormone binds is called binding site. If the molecule is a receptor (like in a cell membrane) the binding site is called a receptor site hormone/receptor site is specific; e.g., epinephrine cannot bind to the receptor site for insulin. The purpose of binding to target tissue is to elicit a response by the target cell. 17-23

Decrease in Receptor Number Normally, receptor molecules are degraded and replaced on a regular basis. Down-regulation Rate at which receptors are synthesized decreases in some cells after the cells are exposed to a hormone. Combination of hormones and receptors can increase the rate at which receptor molecules are degraded. This combined form is taken into the cell by phagocytosis and then broken down. Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Hormone Receptor Hormone Receptor Receptor being removed from plasma membrane Internalized and degraded receptors (a) Down-regulation Plasma membrane Nucleus Time 17-24

Increase in Receptor Number Up-Regulation Some stimulus causes increase in synthesis of receptors for a hormone, thus increases sensitivity to that hormone For example, FSH stimulation of the ovary causes an increase of LH receptors. Ovarian cells are now more sensitive to LH, even if the concentration of LH does not change. This causes ovulation. Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Hormone 1 mrna Receptor being added to plasma membrane New receptors for hormone 2 Time (b) Up-regulation 17-25

Classes of Receptors (a) Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cellular responses DNA Nucleus Hormone Nuclear receptor Lipid-soluble hormone (thyroid or steroid) Lipid-soluble hormones bind to nuclear receptors Hormones Lipid soluble and relatively small molecules; pass through the plasma membrane React either with enzymes in the cytoplasm or with DNA to cause transcription and translation Thyroid hormones, testosterone, estrogen, progesterone, aldosterone, and cortisol 17-26

Classes of Receptors Water-soluble hormones bind to membrane-bound receptors: integral proteins with receptor site at extracellular surface. Interact with hormones that cannot pass through the plasma membrane. Hormones Water-soluble or largemolecular-weight hormones. Attachment of hormone causes intracellular reaction. Large proteins, glycoproteins, polypeptides; smaller molecules like epinephrine and norepinephrine (b) Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. G protein complex Protein kinase Cellular responses Water-soluble hormone (glucagon, prolactin) Membrane-bound receptor ATP camp Adenylate cyclase 17-27

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. TABLE 17.3 Hormone Receptor Types and Mechanisms of Action Hormone Category Receptor Type Hormone Examples Mechanism of Action* Lipid-soluble Nuclear Steroidhormones Testosterone Estrogen Progesterone Aldosterone Cortisol Thyroid hormone Vitamin D Bind hormone to receptor within cell followed by hormone-receptor complex attachment to hormone response element on DNA;results in synthesis of mrna specifc to the particular hormone Water-soluble Membrane-bound Luteinizing hormone F o l l i c l e - s t i m u l a t i n g h o r m o n e Thyroid-stimulating hormone Adrenocorticotropic hormone Glucagon Oxytocin Antidiuretic hormone Calcitonin Parathyroid hormone Activate G proteins Stimulate synthesis of camp Epinephrine Insulin Growth hormone Prolactin Open ion channels *Hormones often exhibit more than one mechanism of action. For simplicity, hormones are listed in only one category. Phosphorylate intracellular proteins 17-28

Action of Nuclear Receptors Proteins in cytoplasm or nucleus Hormones bind with intracellular receptor and receptor-hormone complex activate certain genes, causes transcription of mrna and translation. These proteins (enzymes) produce the response of the target cell to the hormone Latent period of several hours because time is required to produce mrna and protein Processes limited by breakdown of receptorhormone complex Estrogen and testosterone produce different proteins in cells that cause the differing secondary sexual characteristics of females and males. 17-29

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 2 Lipid soluble hormones diffuse through the plasma membrane. Lipid-soluble hormones bind to cytoplasmic receptors and travel to the nucleus or bind to nuclear receptors. Some lipid-soluble hormones bind receptors in the cytoplasm and then move into the nucleus. Lipid soluble hormone 1 Plasma membrane 3 4 5 6 The hormone receptor complex binds to a hormone response element on the DNA, acting as a transcription factor. The binding of the hormone receptor complex to DNA stimulates the synthesis of messenger RNA (mrna), which codes for specific proteins. The mrna leaves the nucleus, passes into the cytoplasm of the cell, and binds to ribosomes, where it directs the synthesis of specific proteins. The newly synthesized proteins produce the cell's response to the lipid soluble hormones for example, the secretion of a new protein. Ribosome mrna 5 6 Proteins produced DNA Hormone response element 4 3 2 Nuclear membrane Nuclear receptor Hormone receptor complex mrna synthesis mrna Nuclear pore 17-30

Membrane-Bound Receptors Intracellular mediators: ions or molecules that enter cell or are produced in cell Can be produced because of G protein activation Regulate intracellular enzyme activities 17-32

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Receptors that Activate G Proteins Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Water soluble hormone Water soluble hormone binds to its receptor. Receptor GDP GTP GTP replaces GDP on subunit. GDP 1 Before the hormone binds to its receptor, the 2 G protein consists of three subunits, with GDP attached to the subunit, and freely floats in the plasma membrane. Water soluble hormone bound to its receptor. After the hormone binds to its membrane-bound receptor, the receptor changes shape, and the G protein binds to it. GTP replaces GDP on the subunit of the G protein. Water soluble hormone separates from its receptor. Receptor 3 G protein separates from receptor. GTP (see part b subunit separates from other subunits. The G protein separates from the receptor. The GTP-linked subunit activates cellular responses, which vary among target cells. (a) Membrane-bound receptors activating G proteins 4 Phosphate (P i ) GDP is removed from GTP on subunit. When the hormone separates from the receptor, additional G proteins are no longer activated. Inactivation of the subunit occurs when phosphate (P i ) is removed from the GTP, leaving GDP bound to the subunit. P i 17-34

G Proteins that open Calcium ion Channels Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ca 2+ Ca 2+ Water soluble hormone bound to receptor Receptor Ca 2+ channel (closed) Ca 2+ channel (open) G protein separates from receptor. GTP GTP replaces GDP on subunit. subunit with GTP binds to Ca 2+ channel and causes it to open. GTP Ca 2+ bound to calmodulin Calmodulin (inactive) Calmodulin (active) 1 After a hormone binds to its receptor, the G protein is 2 activated. The activated subunit with GTP bound to it separates from the and subunits. The subunit, with GTP bound to it, binds to the Ca 2+ channel, and the combination causes the Ca 2+ channel to open. The Ca 2+ diffuse into the cell and combine with calmodulin. The combination of Ca 2+ with calmodulin produces the cell s response to the hormone. Ca 2+ Ca2+ Water soluble hormone separates from receptor Ca 2+ channel (closed) Ca 2+ channel (closed) GDP P i Calmodulin (inactive) Phosphate is removed from GTP on subunit. 3 Phosphate is removed from the GTP bound to the subunit, 4 leaving GDP bound to the subunit. The subunit can no longer stimulate a cellular response; it separates from the Ca 2+ channel, and the channel closes. GDP G protein with GDP bound to the subunit Calmodulin (inactive) The subunit recombines with the and β subunits. 17-36

G Proteins that Interact with Adenylate Cyclase Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 2 After a water-soluble hormone binds to its receptor, the G protein is activated. The activated α subunit, with GTP bound to it, binds to and activates an adenylate cyclase enzyme, so that it converts ATP to camp. 1 Water soluble hormone bound to its receptor. 3 4 The camp can activate protein kinase enzymes, which phosphorylate specific enzymes activating them. The chemical reactions catalyzed by the activated enzymes produce the cell's response. Phosphodiesterase enzymes inactivate camp by converting camp to AMP. γ β α From part a GTP 2 ATP Adenylate cyclase 3 Protein kinase camp camp is an intracellular mediator that activates protein kinases. Phosphodiesterase inactivates camp. 4 AMP (inactive) Cellular responses (b) Membrane-bound receptors that interact with adenylate cyclase 17-38

G Proteins that Interact with other Intercellular Mediators Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 Epinephrine binds to its receptor in the smooth muscle plasma membrane. Epinephrine bound to receptor 1 Phospholipase C 2 The G protein is activated. The activated subunit with GTP bound to it separates from the and β subunits. 3 The activated subunit then binds with phospholipase C, which acts on phosphoinositol bisphosphate (PIP 2 ) and produces inositol triphosphate (IP 3 ) and diacylglycerol (DAG). 4 IP 3 Ca 2+ 2 GTP 3 PIP 2 4 5 IP releases Ca 2+ from the endoplasmic reticulum or opens Ca 2+ channels in the plasma membrane. Calcium ions then regulate enzyme activity. DAG regulates enzymes such as protein kinases and those that synthesize prostaglandin. These responses increase smooth muscle contraction. Ca 2+ Endoplasmic reticulum Calmodulin 5 Response DAG Protein kinase 17-39

Receptors That Directly Alter the Activity of Intracellular Mediator 1 Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Thewater-soluble hormone binds to its receptor. Water-soluble hormone 1 2 At the inner surface of the plasma membrane, guanylate cyclase is activated to produce cgmp from GTP. 3 4 Cyclic GMP is an Intracellular mediator that alters the activity of other Intracellular enzymes to produce the response of the cell. Phosphodiesterase is an enzyme that converts cgmp to inactive GMP. GTP 3 Response 2 cgmp Guanylate cyclase (activated) Phosphodiesterase (inactivates cgmp) 4 GMP (inactive) 17-41

Receptors That Phosphorylate Intracellular Proteins Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 Unphosphorylated receptor and proteins Hormone Membrane-bound receptor The membrane-bound receptor and other proteins have sites that can be phosphorylated at the inner surface of the plasma membrane. When the receptor is not bound to a hormone, these sites remain unphosphorylated. P P P P Hormone bound to its receptor. Hormones bind to membrane-bound receptors. Part of receptor protein on inside of membrane acts as an enzyme to phosphorylate proteins E.g., insulin receptors bound to insulin cause phosphorylation of proteins and cell responds to presence of insulin. P P P P Phosphorylated receptor and proteins result in the cell response. 2 The hormone binds to its receptor site on the outside of the plasma membrane. The receptor acts as an enzyme that phosphorylates the sites on the receptor and associated proteins. These phosphorylated proteins produce a response inside the cell. 17-42

Signal Amplification Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Receptor Hormone Activated G proteins Activated adenylate cyclase camp Activated protein kinase enzymes 17-43