16 - Greenwood High School

16 The Endocrine System: Part A Endocrine System: Overview* Acts with the nervous system to coordinate and integrate the activity of body cells Influences metabolic activities by means of hormones transported in the blood Responses occur more slowly but tend to last longer than those of the nervous system Endocrine glands: pituitary, thyroid, parathyroid, adrenal, and pineal glands Endocrine System: Overview* Some organs produce both hormones and exocrine products (e.g., pancreas and gonads) The hypothalamus has both neural and endocrine functions Other tissues and organs that produce hormones include adipose cells, thymus, cells in the walls of the small intestine, stomach, kidneys, and heart

Pineal gland Hypothalamus Pituitary gland Thyroid gland Parathyroid glands (on dorsal aspect of thyroid gland) Thymus Adrenal glands Pancreas Ovary (female) Testis (male) Figure 16.1 Chemical Messengers* Hormones: long-distance chemical signals that travel in the blood or lymph Autocrines: chemicals that exert effects on the same cells that secrete

them Paracrines: locally acting chemicals that affect cells other than those that secrete them Autocrines and paracrines are local chemical messengers and will not be considered part of the endocrine system Figure 11.5 Local signaling Electrical signal triggers release of neurotransmitter. Target cells Neurotransmitter diffuses across synapse. Secreting cell

Secretory vesicles Target cell Local regulator (a) Paracrine signaling (b) Synaptic signaling Long-distance signaling Endocrine cell Target cell specifically binds hormone. Hormone travels in bloodstream. Blood

vessel (c) Endocrine (hormonal) signaling Chemistry of Hormones* Two main classes 1. Amino acid-based hormones Amines, thyroxine, peptides, and proteins 2. Steroids Synthesized from cholesterol Gonadal and adrenocortical hormones Mechanisms of Hormone Action* Hormone action on target cells 1. Alter plasma membrane permeability of membrane potential by opening or closing ion channels 2. Stimulate synthesis of proteins or regulatory molecules 3. Activate or deactivate enzyme systems 4. Induce secretory activity 5. Stimulate mitosis

Mechanisms of Hormone Action* Two mechanisms, depending on their chemical nature 1. Water-soluble hormones (all amino acidbased hormones except thyroid hormone) Cannot enter the target cells Act on plasma membrane receptors Coupled by G proteins to intracellular second messengers that mediate the target cells response Mechanisms of Hormone Action* 2. Lipid-soluble hormones (steroid and thyroid hormones) Act on intracellular receptors that directly activate genes Couple of things to remember so the following slides dont sound like Greek -ase on a word means it is an enzyme To phosphorylate a molecule means to add a phosphate group to it

(PO4) A kinase is an enzyme that phosphorylates something, i.e. adds a phosphate group. Plasma Membrane Receptors and Second-Messenger Systems* cAMP signaling mechanism 1. 2. 3. 4. 5. Hormone (first messenger) binds to receptor Receptor activates G protein G protein activates adenylate cyclase Adenylate cyclase converts ATP to cAMP (second messenger) cAMP activates protein kinases Plasma Membrane Receptors and Second-Messenger Systems* (For

water based) 6. cAMP signaling mechanism Activated kinases phosphorylate various proteins, activating some and inactivating others cAMP is rapidly degraded by the enzyme phosphodiesterase Intracellular enzymatic cascades have a huge amplification effect 1 Hormone (1st messenger) binds receptor. Adenylate cyclase Extracellular fluid G protein (GS) 5 cAMP acti- vates protein

kinases. Receptor GDP Hormones that act via cAMP mechanisms: Epinephrine ACTH FSH LH Glucagon PTH TSH Calcitonin 2 Receptor activates G protein (GS).

3 G protein 4 Adenylate activates cyclase adenylate converts ATP cyclase. to cAMP (2nd messenger). Active protein kinase Triggers responses of target cell (activates enzymes, stimulates cellular secretion, opens ion channel, etc.) Cytoplasm Inactive

protein kinase Figure 16.2 1 Hormone (1st messenger) Extracellular fluid binds receptor. Receptor Hormones that act via cAMP mechanisms: Epinephrine ACTH FSH LH Glucagon

PTH TSH Calcitonin Cytoplasm Figure 16.2, step 1 1 Hormone (1st messenger) Extracellular fluid binds receptor. G protein (GS) Receptor GDP Hormones that act via cAMP mechanisms:

Epinephrine ACTH FSH LH Glucagon PTH TSH Calcitonin 2 Receptor activates G protein (GS). Cytoplasm Figure 16.2, step 2 1 Hormone (1st messenger) binds receptor.

Adenylate cyclase Extracellular fluid G protein (GS) Receptor GDP Hormones that act via cAMP mechanisms: Epinephrine ACTH FSH LH Glucagon PTH TSH Calcitonin

2 Receptor activates G protein (GS). 3 G protein activates adenylate cyclase. Cytoplasm Figure 16.2, step 3 1 Hormone (1st messenger) binds receptor. Adenylate cyclase Extracellular fluid

G protein (GS) Receptor GDP Hormones that act via cAMP mechanisms: Epinephrine ACTH FSH LH Glucagon PTH TSH Calcitonin 2 Receptor activates G protein (GS).

3 G protein 4 Adenylate activates cyclase adenylate converts ATP cyclase. to cAMP (2nd messenger). Cytoplasm Figure 16.2, step 4 1 Hormone (1st messenger) binds receptor. Adenylate cyclase Extracellular fluid

G protein (GS) 5 cAMP acti- vates protein kinases. Receptor GDP Hormones that act via cAMP mechanisms: Epinephrine ACTH FSH LH Glucagon PTH TSH

Calcitonin 2 Receptor activates G protein (GS). 3 G protein 4 Adenylate activates cyclase adenylate converts ATP cyclase. to cAMP (2nd messenger). Active protein kinase Triggers responses of target cell (activates enzymes, stimulates

cellular secretion, opens ion channel, etc.) Cytoplasm Inactive protein kinase Figure 16.2, step 5 http://www.bozemanscience.com/038-signal-transduction-pathways The Three Stages of Cell Signaling: A Preview Earl W. Sutherland discovered how the hormone epinephrine acts on cells Sutherland suggested that cells receiving signals went through three processes Reception Transduction Response

In reception, the target cell detects a signaling molecule that binds to a receptor protein on the cell surface In transduction, the binding of the signaling molecule alters the receptor and initiates a signal transduction pathway; transduction often occurs in a series of steps In response, the transduced signal triggers a specific response in the target cell Figure 11.6-1 EXTRACELLULAR FLUID 1 Reception Receptor Signaling molecule

CYTOPLASM Plasma membrane Figure 11.6-2 EXTRACELLULAR FLUID 1 CYTOPLASM Plasma membrane Reception 2 Transduction Receptor 1

2 Relay molecules Signaling molecule 3 Figure 11.6-3 EXTRACELLULAR FLUID 1 CYTOPLASM Plasma membrane Reception 2

Transduction 3 Response Receptor 1 2 Relay molecules Signaling molecule 3 Activation of cellular response

Concept 11.2: Reception: A signaling molecule binds to a receptor protein, causing it to change shape The binding between a signal molecule (ligand) and receptor is highly specific A shape change in a receptor is often the initial transduction of the signal Most signal receptors are plasma membrane proteins Receptors in the Plasma Membrane G protein-coupled receptors (GPCRs) are the largest family of cellsurface receptors Most water-soluble signal molecules bind to specific sites on receptor proteins that span the plasma membrane There are three main types of membrane receptors G protein-coupled receptors Receptor tyrosine kinases Ion channel receptors G protein-coupled receptors (GPCRs) are cell surface transmembrane receptors that work with the help of a G protein

G proteins bind the energy-rich GTP G proteins are all very similar in structure GPCR systems are extremely widespread and diverse in their functions Receptor tyrosine kinases (RTKs) are membrane receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Abnormal functioning of RTKs is associated with many types of cancers A ligand-gated ion channel receptor acts as a gate when the receptor changes shape When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor Figure 11.8a Signaling molecule binding site

Segment that interacts with G proteins G protein-coupled receptor Figure 11.8b G protein-coupled receptor Plasma membrane Activated receptor Inactive enzyme GTP GDP

GDP CYTOPLASM Signaling molecule G protein (inactive) GDP Enzyme GTP 2 1

Activated enzyme GTP GDP Pi Cellular response 3 4 Figure 11.8ba G protein-coupled receptor Plasma membrane

GDP CYTOPLASM G protein (inactive) Enzyme 1 Signaling molecule Activated receptor GTP GDP GDP 2

GTP Inactive enzyme Figure 11.8bb Activated enzyme GTP Cellular response 3 GDP Pi

4 Figure 11.8c Signaling molecule (ligand) helix in the Signaling molecule Ligand-binding site membrane Tyrosines CYTOPLASM Tyr Tyr

Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr

Tyr Tyr Tyr Tyr Tyr Tyr Receptor tyrosine kinase proteins (inactive monomers) Dimer 2 1

Activated relay proteins Tyr Tyr P Tyr Tyr P Tyr Tyr Tyr Tyr P Tyr

P Tyr Tyr P Tyr P 6 ATP Activated tyrosine kinase regions (unphosphorylated dimer) 3 6 ADP Fully activated receptor tyrosine kinase (phosphorylated dimer) P Tyr

Tyr P P Tyr P Tyr Tyr P Tyr P Inactive relay proteins 4 Cellular response 1 Cellular response 2 Figure 11.8ca

Signaling molecule (ligand) helix in the Ligand-binding site membrane Tyrosines CYTOPLASM 1 Tyr Tyr Tyr Tyr

Tyr Tyr Receptor tyrosine kinase proteins (inactive monomers) Figure 11.8cb Signaling molecule Tyr Tyr Tyr Tyr Tyr

Tyr Tyr Tyr Tyr Tyr Tyr Tyr Dimer 2 Figure 11.8cc

Tyr Tyr P Tyr Tyr Tyr P Tyr Tyr P Tyr P Tyr Tyr P Tyr

Tyr P 6 ATP Activated tyrosine kinase regions (unphosphorylated dimer) 3 6 ADP Fully activated receptor tyrosine kinase (phosphorylated dimer) Figure 11.8cd Activated relay

proteins P Tyr Tyr P P Tyr Tyr P P Tyr Tyr P Inactive relay proteins 4 Cellular response 1 Cellular

response 2 Figure 11.8d-1 1 Signaling molecule (ligand) Gate closed Ligand-gated ion channel receptor Ions Plasma membrane

Figure 11.8d-2 1 Signaling molecule (ligand) Gate closed Ligand-gated ion channel receptor 2 Ions Plasma membrane

Gate open Cellular response Figure 11.8d-3 1 Signaling molecule (ligand) Gate closed Ligand-gated ion channel receptor 3 2

Ions Gate open Cellular response Plasma membrane Gate closed Signal Transduction Pathways The binding of a signaling molecule to a receptor triggers the first step in a chain of molecular interactions Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated At each step, the signal is transduced into a different form, usually a shape change in a protein

Protein Phosphorylation and Dephosphorylation Phosphorylation and dephosphorylation of proteins is a widespread cellular mechanism for regulating protein activity Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation Many relay molecules in signal transduction pathways are protein kinases, creating a phosphorylation cascade Figure 11.10 Signaling molecule Receptor Activated relay molecule Inactive protein kinase

1 sp ATP PP e ad sc Inactive protein kinase 3 ca Pi P

Active protein kinase 2 n io ADP t la ry ho Inactive protein kinase 2 o

Ph Active protein kinase 1 ATP ADP Pi Active protein kinase 3 PP Inactive protein

P ATP P ADP Pi PP Active protein Cellular response Figure 11.10a Signaling molecule

Receptor Inactive protein kinase 1 Activated relay molecule Active protein kinase 1 Figure 11.10b Phosphorylation cascade Inactive protein kinase

1 Active protein kinase 1 Inactive protein kinase 2 Pi ATP ADP Active protein kinase 2 PP Inactive

protein kinase 3 Pi P ATP ADP PP Active protein kinase 3 P Figure 11.10c Inactive protein kinase

3 Pi ATP ADP Active protein kinase 3 PP Inactive protein P ATP ADP Pi

PP P Active protein Cellular response Protein phosphatases rapidly remove the phosphates from proteins, a process called dephosphorylation This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off or up or down, as required Small Molecules and Ions as Second Messengers Many signaling pathways involve second messengers Second messengers are small, nonprotein, water-soluble molecules or

ions that spread throughout a cell by diffusion Second messengers participate in pathways initiated by GPCRs and RTKs Cyclic AMP and calcium ions are common second messengers Cyclic AMP Cyclic AMP (cAMP) is one of the most widely used second messengers Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal Understanding of the role of cAMP in G protein signaling pathways helps explain how certain microbes cause disease The cholera bacterium, Vibrio cholerae, produces a toxin that modifies a G protein so that it is stuck in its active form This modified G protein continually makes cAMP, causing intestinal cells to secrete large amounts of salt into the intestines Water follows by osmosis and an untreated person can

soon die from loss of water and salt Other pathways regulate the activity of enzymes rather than their synthesis For example, a signal could cause opening or closing of an ion channel in the plasma membrane, or a change in cell metabolism Figure 11.16 Reception Binding of epinephrine to G protein-coupled receptor (1 molecule) Transduction Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102)

ATP Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Inactive phosphorylase kinase Response Active phosphorylase kinase (105) Glycogen Glucose 1-phosphate (108 molecules) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Figure 11.16a

Reception Binding of epinephrine to G protein-coupled receptor (1 molecule) Response Glycogen Glucose 1-phosphate (108 molecules) Figure 11.16b Transduction Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104)

Inactive protein kinase A Active protein kinase A (104) Figure 11.16c Transduction Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Signaling pathways can also affect the overall behavior of a cell, for example, a signal could lead to cell division

Regulation ofa signal themayResponse A response to not be simply on or off There are four aspects of signal regulation to consider Amplification of the signal (and thus the response) Specificity of the response Overall efficiency of response, enhanced by scaffolding proteins Termination of the signal Intracellular Receptors Intracellular receptor proteins are found in the cytoplasm or nucleus of target cells Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors Examples of hydrophobic messengers are the steroid and thyroid hormones of animals An activated hormone-receptor complex can act as a transcription

factor, turning on specific genes Intracellular Receptors and Direct Gene Activation* Steroid hormones and thyroid hormone 1.Diffuse into their target cells and bind with intracellular receptors 2.Receptor-hormone complex enters the nucleus 3.Receptor-hormone complex binds to a specific region of DNA 4.This prompts DNA transcription to produce mRNA 5.The mRNA directs protein synthesis Steroid hormone Plasma membrane Extracellular fluid 1 The steroid hormone

diffuses through the plasma membrane and binds an intracellular receptor. Cytoplasm Receptor protein Receptorhormone complex 2 The receptor- Nucleus Hormone response elements DNA mRNA hormone complex enters

the nucleus. 3 The receptor- hormone complex binds a hormone response element (a specific DNA sequence). 4 Binding initiates transcription of the gene to mRNA. 5 The mRNA directs protein synthesis. New protein Figure 16.3 Steroid hormone Extracellular fluid

Plasma membrane 1 The steroid hormone diffuses through the plasma membrane and binds an intracellular receptor. Cytoplasm Receptor protein Receptorhormone complex Nucleus Figure 16.3, step 1

Steroid hormone Extracellular fluid Plasma membrane 1 The steroid hormone diffuses through the plasma membrane and binds an intracellular receptor. Cytoplasm Receptor protein Receptorhormone complex 2 The receptor-

Nucleus hormone complex enters the nucleus. Figure 16.3, step 2 Steroid hormone Extracellular fluid Plasma membrane 1 The steroid hormone diffuses through the plasma membrane and binds an intracellular receptor. Cytoplasm

Receptor protein Receptorhormone complex 2 The receptor- Nucleus Hormone response elements DNA hormone complex enters the nucleus. 3 The receptor- hormone complex binds a hormone response element (a specific DNA sequence).

Figure 16.3, step 3 Steroid hormone Extracellular fluid Plasma membrane 1 The steroid hormone diffuses through the plasma membrane and binds an intracellular receptor. Cytoplasm Receptor protein Receptorhormone

complex 2 The receptor- Nucleus Hormone response elements DNA mRNA hormone complex enters the nucleus. 3 The receptor- hormone complex binds a hormone response element (a specific DNA sequence). 4 Binding initiates transcription of the

gene to mRNA. Figure 16.3, step 4 Steroid hormone Plasma membrane Extracellular fluid 1 The steroid hormone diffuses through the plasma membrane and binds an intracellular receptor. Cytoplasm Receptor protein

Receptorhormone complex 2 The receptor- Nucleus Hormone response elements DNA mRNA hormone complex enters the nucleus. 3 The receptor- hormone complex binds a hormone response element (a specific DNA sequence). 4 Binding initiates

transcription of the gene to mRNA. 5 The mRNA directs protein synthesis. New protein Figure 16.3, step 5 Target Cell Specificity* Target cells must have specific receptors to which the hormone binds ACTH receptors are only found on certain cells of the adrenal cortex Thyroxin receptors are found on nearly all cells of the body Target Cell Activation* Target cell activation depends on three factors 1. Blood levels of the hormone 2. Relative number of receptors on or in the target cell 3. Affinity of binding between receptor and hormone

Target Cell Activation* Hormones influence the number of their receptors Up-regulationtarget cells form more receptors in response to the hormone Down-regulationtarget cells lose receptors in response to the hormone Hormones in the Blood* Hormones circulate in the blood either free or bound Steroids and thyroid hormone are attached to plasma proteins All others circulate without carriers The concentration of a circulating hormone reflects: Rate of release Speed of inactivation and removal from the body Hormones in the Blood* Hormones are removed from the blood by

Degrading enzymes Kidneys Liver Half-lifethe time required for a hormones blood level to decrease by half Control of Hormone Release* Blood levels of hormones Are controlled by negative feedback systems Vary only within a narrow desirable range Hormones are synthesized and released in response to 1. Humoral stimuli (blood) 2. Neural stimuli (nerves) 3. Hormonal stimuli (other hormones) Humoral Stimuli* Changing blood levels of ions and nutrients directly stimulates

secretion of hormones Example: Ca2+ in the blood Declining blood Ca2+ concentration stimulates the parathyroid glands to secrete PTH (parathyroid hormone) PTH causes Ca2+ concentrations to rise and the stimulus is removed (a) Humoral Stimulus 1 Capillary blood contains low concentration of Ca2+, which stimulates Capillary (low Ca2+ in blood) Thyroid gland Parathyroid (posterior view) glands PTH Parathyroid

glands 2 secretion of parathyroid hormone (PTH) by parathyroid glands* Figure 16.4a Neural Stimuli* Nerve fibers stimulate hormone release Sympathetic nervous system fibers stimulate the adrenal medulla to secrete catecholamines (b) Neural Stimulus 1 Preganglionic sympathetic fibers stimulate adrenal medulla cells CNS (spinal cord) Preganglionic

sympathetic fibers Medulla of adrenal gland Capillary 2 to secrete catechola- mines (epinephrine and norepinephrine) Figure 16.4b Hormonal Stimuli* Hormones stimulate other endocrine organs to release their hormones Hypothalamic hormones stimulate the release of most anterior pituitary hormones Anterior pituitary hormones stimulate targets to secrete still more hormones Hypothalamic-pituitary-target endocrine organ feedback loop: hormones from the final target organs inhibit the release of the anterior pituitary

hormones (c) Hormonal Stimulus 1 The hypothalamus secretes hormones that Hypothalamus 2 stimulate the anterior pituitary gland to secrete hormones that Thyroid gland Adrenal

cortex Pituitary gland Gonad (Testis) 3 stimulate other endocrine glands to secrete hormones Figure 16.4c Nervous System Modulation* The nervous system modifies the stimulation of endocrine glands and their negative feedback mechanisms Example: under severe stress, the hypothalamus and the sympathetic nervous system are activated As a result, body glucose levels rise

The Pituitary Gland and Hypothalamus The pituitary gland (hypophysis) has two major lobes 1. Posterior pituitary (lobe): 2. Anterior pituitary (lobe) (adenohypophysis) Pituitary-Hypothalamic Relationships* Posterior lobe synthesizes the neurohormones oxytocin and antidiuretic hormone (ADH) Neurohormones are transported to the posterior pituitary 1 Hypothalamic Paraventricular nucleus Supraoptic nucleus Optic chiasma Infundibulum (connecting stalk)

Hypothalamichypophyseal tract Axon terminals Posterior lobe of pituitary Hypothalamus neurons synthesize oxytocin and ADH. 2 Oxytocin and ADH are Inferior hypophyseal artery transported along the hypothalamic-hypophyseal tract to the posterior

pituitary. 3 Oxytocin and ADH are stored in axon terminals in the posterior pituitary. 4 Oxytocin and ADH are Oxytocin ADH released into the blood when hypothalamic neurons fire. (a) Relationship between the posterior pituitary and the hypothalamus Figure 16.5a Hypothalamus Hypothalamic neuron cell bodies

Superior hypophyseal artery Hypophyseal portal system Primary capillary plexus Hypophyseal portal veins Secondary capillary plexus Anterior lobe of pituitary TSH, FSH, LH, ACTH, GH, PRL 1 When appropriately stimulated, hypothalamic neurons

secrete releasing and inhibiting hormones into the primary capillary plexus. 2 Hypothalamic hormones travel through the portal veins to the anterior pituitary where they stimulate or inhibit release of hormones from the anterior pituitary. 3 Anterior pituitary hormones are secreted into the secondary capillary plexus. (b) Relationship between the anterior pituitary and the hypothalamus Figure 16.5b

Anterior Pituitary Hormones Growth hormone (GH) Thyroid-stimulating hormone (TSH) or thyrotropin Adrenocorticotropic hormone (ACTH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Prolactin (PRL) Anterior Pituitary Hormones All are proteins All except GH activate cyclic AMP second-messenger systems at their targets TSH, ACTH, FSH, and LH are all tropic hormones (regulate the secretory action of other endocrine glands) Growth Hormone (GH)* Stimulates most cells, but targets bone and skeletal muscle Promotes protein synthesis and encourages use of fats for fuel

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