Endocrine System and Signal Transduction

1. Endocrine System and Signal Transduction Dr. Jason R Mayberry Castle View High School

2. Reproductive Nervous Endocrine Digestive Respiratory Urinary Cardiovascular Immune Integumentary Muscular Skeletal Organ Systems

3. System Comparisions Hypothalamus ENDOCRINE SYSTEM EXOCRINE GLANDS NERVOUS SYSTEM Pituitary Pineal Gland Functions Homoeostasis - slower developing but longer lasting effects;Regulate growth and energy utilization, etc. Thermoregulation (Sweat), Digestion, Milk Production, etc. Homeostasis - fast acting but shorter duration;Movement, Sensory Processing, Behavior, Endocrine Function. Thyroid Parathyroid Thymus How Elicit Responses Hormones secreted from ductless gland travel in Blood stream to target tissues Molecules secreted into ducts leading to lumen of GI tract or outside the body Neurons conduct electrical impulses from stimulus to target cells. Adrenal Functional Molecules Hormones: signaling molecules that circulate through the bloodstream Digestive Enzymes, Sweat, Saliva, Milk, etc. Neurotransmitters: Paracrine signaling molecules Pancreas Gonads OH O Exocrine Pancreas HO OH O Salivary Glands

4. Long-Distance Signaling • Endocrine signaling (Glands): • A ductless gland releases hormones into the bloodstream. The blood stream caries the hormone throughout the body. Bloodvessel Response Synapse • Synaptic signaling (Neurons): • A neuron releases neurotransmitters on a cell with receptors for the transmitter (paracrine) Neuron Response • Neuroendocrine signaling: • A neuron releases neurohormones into the blood stream. • The blood stream caries the neurohormone to its target. Neurosecretorycell Bloodvessel Response

5. Endocrine Organs • Anterior pituitary gland • Subregulatory • Hypothalamus • Master Regulatory Posterior pituitary gland Heart Pineal Liver Parathyroids Adrenal gland (medulla and cortex) Thyroid Stomach kidneys Small intestine Pancreas Ovaries (in females) Testes (in males) Adipose tissue

6. Classification of Hormone Action • Trophic Hormones (also called Tropic) • Hormones that target another endocrine gland and stimulate production and/or release of another hormone • Non-Trophic Hormones • Opening/closing of ion channels • Activates or deactivates enzymes already present in the cytosol • Induces Secretory activity of stored molecules • Target Cytoskeletal proteins Endocrine Gland Endocrine Gland Trophic Hormone Non-Trophic Hormone Endocrine Gland Non-Trophic Hormone Response has physiological effects Response has physiological effects

7. γ γ β β One Hormone – Many Functions Effects of Epinephrine Given: all cells are exposed to any hormone released into the blood stream. Question: Why don’t they all have the same response? Dilates pupils Relaxes airways Inhibits salivation (production of saliva) Speeds heart rate Answer: They cell may or may not have a receptor Different receptors may recognize the same hormone Different Intracellular Proteins may be activated/inhibited CH2OH Stimulates glucose O H H H H OH HO OH Stimulates sweating H OH α α Constricts blood vessels in the skin GDP GDP Cascade A Cascade B Cascade C No Response Response A Response B Response C Kidney Tubule Muscle Liver Brain

8. Same receptors but differentintracellular proteins (not shown) Different receptors Different cellularresponses Different cellularresponses Figure 45.9 Epinephrine Epinephrine Epinephrine  receptor  receptor  receptor Glycogendeposits Vesseldilates. Vesselconstricts. Glycogenbreaks downand glucoseis releasedfrom cell. Skeletal muscleblood vessel Liver cell Intestinal bloodvessel

9. How do hormones elicit a response

10. Types of Cell-Cell Signals in Multicellular Organisms Local Signaling Direct Cytosolic: Signals such as ions and small signaling molecules pass directly between cells through gap junctions Paracrine: Signals between neighboring cells where the signalling molecule is released into the extracellular space. Autocrine: When a cell signals to itself (makes both the signaling molecule and the receptor) Juxtacrine(Contact-Dependent): Signals between neighboring cells where the signaling molecules is bound to one of the cell’s surface OH O HO OH O e.g. Cardiac muscle cells e.g. Axon Growth, certain immune responses e.g. Neuron-neuron via neurotransmitters e.g. Density dependent growth. Long Distance Signaling Note: Cell Signalling is also essential for single cellular organisms, though we will generally focus on multicellular organisms Endocrine: Signaling molecules are released into the blood stream and affect cells over great distances throughout the body

11. How does a Cell know what to do? • Housekeeping genes and functions: always active to maintain basic cellular function • Response/Conditional genes and functions: induced by the presence of some external molecule or condition (often necessary to sustain life) • How are conditional responses initiated within cells? • Considerations: • Plasma membrane is an effective barrier preventing most external molecules from entering the cell • Cell responses require chemistry, which requires physical contact between molecules Conditional Intracellular Response Gene Enhancer Prom.

12. General Aspects of Cell Signaling • Signalling Molecule: Molecule found in a cell’s environment (e.g. Hormones, pheromones, sugars, etc) • Receptor: Protein that binds reversibly to a specific signaling molecule and initiates a cellular response • Transmembrane (Integral) receptors detect signals that do not cross the membrane (usually hydrophilic molecules) • Cytosolic receptors detect molecules that cross the plasma membrane (usually lipophilic) • To respond to a signal, a cell must have a Receptor for the specific molecule • Types of Receptors • Chemoreceptors: respond to molecules from outside the cell known as the Ligand (depicted here) • Mechanoreceptors: respond to force, touch, or vibration • Thermoreceptors: respond to temperature changes • Photoreceptors: respond to light Gene Enhancer Prom.

13. c) b) a) LatentEnzyme R-PII General Aspects of Cell Signaling • Signal Transduction: sequence of events molecular interactions within a cell beginning with a signaling molecule binding to a receptor and leading to a cellular response to a signal • Binding and Conformational change: ligand binds reversibly to receptor causing a shape change affecting the intracellular portion • Signal Transduction Cascade/Pathway: • Intracellular molecules detect change in receptor shape • the “message” is often passed from one molecule to another until the final target is reached. • Second messengers small, non protein components of a cascade that diffuse quickly through the cytosol and activate downstream proteins • Cellular Response: cells can respond to a signal in three general ways: • Activation of Transcription Factors • Activation of Latent Enzymes in the cytosol • Alteration of the cytoskeleton to initiate shape changes or cell migration. Gene Enhancer Prom.

14. Advantages of 2nd Messengers • Second Messengers: • Small, non-protein molecules involved in signal transduction pathways that diffuse rapidly through the cytosol and are capable of activating many downstream targets • Advantages: • Amplification: at each stage the number of targets affected increase • Speed: because they are usually small, second messengers diffuse rapidly throughout the cell. Signal/receptor cAMP (2ndMsngr) Activated PKA Target protein phosphorylated by PKA

15. Different Properties of Hormone Signaling Molecules Hydrophilic Signaling Molecules Lipophilic Signaling Molecules How they exit the cell in which they are produced Cannot cross the plasma membrane so are exocytosed(secreted) Can be storedin secretory vesicles Pass freely through plasma membranes so diffuseout of the cell Cannot be stored in secretory vesicles SECRETORYCELL How they travel through the blood stream Dissolve in plasma Do not dissolve in plasma so have protein carriers that transport them VIABLOOD Transport/Carrierprotein Signal receptor TARGETCELL OR Location of their receptors Have cell surface receptors and work through second messengers and signaling cascades Cross freely through the plasma membrane so have intracellular receptors (cytosol or nucleus). Signalreceptor Cytoplasmicresponse Generegulation Cytoplasmicresponse Generegulation NUCLEUS Typical Cellular Response Cytosolic Effects and/or Gene regulation Gene Regulation Campbell Biology Figure 45.6-2

16. Hormone Examples Hydrophylic Lipophylic (e.g. steroids) • All Hypothalamic Hormones (not listed here) • All Pituitary Hormones (not listed here) • Epinephrine • Insulin • Glucagon • Parathyroid Hormone • Calcitonin • Insulin-Like Growth Factor (IGF) • Thyroid Hormone (T3 and T4) (But are treated as if they were Lipophylic) • Adrenal Cortex Hormones and major Gonadal Hormones • Estrogens (Estradiol, Estrone, Estriol) • Progesterone • Testosterone • Aldosterone • Cortisol

17. Types of Hormones/Signaling Molecules • Amines: Amino Acids derived from the amino acid Tyrosine • Peptides and Proteins: 3 to 211 amino acids • Steroids: derived from Cholesterol • Small Permeable: Many small molecules such as Nitrous Oxide, Carbon Dioxide, etc.

18. OH HO CH2 OH H2N CH2 H2N COOH OH HO OH OH I I I I I I I OH H2N O O CH2 CH2 H2N H2N COOH COOH Tyrosine Dopamine Produced in Hypothalamus Epinephrine Produced in Adrenal Medulla Thyroxine (T4) Triiodothyronine (T3) Amines • Modified Amino Acids • Hydrophilic, so cannot pass freely through the plasma membrane • Two classes: • Catecholamine • Derived from the amino acid Tyrosine • A second ”OH” added to the phenyl group Exit Cell: Secreted Blood stream: Free Receptor Type: Cell-Surface Effects: Cytosolic • Thyroid Hormones • Derived from Tyrosine • Contains Iodine residues on the phenyl groups (cyclic 6 carbon rings) Exit Cell: Secreted Blood stream: *Bound (mostly) Receptor Type: *Intracellular Effects: *Gene Regulation

19. Insulin from the beta cells of the pancreas islets of langerhans Many other hormones have a similar structure (FSH, LH, HCG, Somatomedins) Growth Hormone released by the Anterior Pituitary Oxytocin released by the Hypothalamus through the Posterior Pituitary Peptides and Proteins • Range from 3 to 211 amino acid residues • Hydrophilic • Produced by a majority of Endocrine Glands (Hypothalamus, Pituitary, Parathyroid, Thymus, Pancreas) Exit Cell: Secreted Blood stream: Free Receptor Type: Cell-Surface Effects: Cytosolic

20. OH OH Cholesterol O O O O OH OH Estradiol testosterone O Progesterone OH O HO OH OH Estrone OH O O OH Cortisol O OH OH OH O O Cortisone(inactive) O HO OH OH Estriol Aldosterone Steroids Exit Cell: Diffusion Blood stream: Bound Receptor Type: Intracellular Effects: Gene Regulation • Steroids are all derived from Cholesterol • Produced by the Adrenal Cortex, Gonads, and placenta • Lipophilic

21. γ β Receptor Types • Different Hormones bind to predictable Classes of Receptors • Non Steroid Receptors do not pass through the plasma membrane and have cell-surface receptors • GPCR/7-passTransmembrane receptors are G-protein coupled Receptors (e.g. epinephrine, TSH) • Receptor Tyrosine Kinases (RTK) (single pass) work through SH-2 proteins (e.g. Insulin and Glucagon) • 4-passTransmembrane receptors come together in groups of 5 to make an ion channel (e.g. neurotransmitters) • Steroid Receptors (and thyroid hormone receptors) are found within the cytosol or nucleus α GDP G-Protein Second Messengers and Signaling Cascades Second Messengers and Signaling Cascades

22. H+ H+ O– O– H+ O– O O P P O O O P O NH2 NH2 NH2 O– O– H+ H+ O C C C N N N C C C N N N A A A HC HC HC C C C C C C N N N N N N H H H γ γ β β O NH2 O P C N C N A H+ O– HC O O C C N N H2C H P O H+ O O P – O H+ O– H+ O– H CH2 CH2 CH2 O O O OH OH OH OH H H G-Protein Coupled Receptors (GPCR) with AdenylateCyclase • Hormone (first messenger) Binds to GPCR • Receptor undergoes a conformational change • G-proteins bind to receptor • α-subunit releases GDP and bind with GTP • α-subunit breaks free and moves along plasma membrane to AdenylateCyclase • AdenylateCyclase converts ATP to cyclic AMP (cAMP; the “second messenger”) • 4 molecules of cAMP bind to cAMP dependent Protein Kinase (PKA) • cAMP is produced until GTP is hydrolized • Catalytic subunits of PKA break free and activate cytosolic enzymes by adding a phosphate group to them (i.e. Kinasing) • Phosphodiesterase(PDE) converts cAMP to AMP, deactivating PKA • Note: some g-proteins replace the α (activating) subunit with an “i” (inhibiting). Catecholamine, Peptide, or Protein AdenylateCyclase α α GDP GDP GDP GPCR(7-Pass) G-Protein cAMP ATP ATP ATP ATP ATP GTP PDE cAMP dependent PKA cAMP cAMP AMP AMP cAMP cAMP AMP cAMP cAMP AMP cAMP cAMP P P Inactive Enzymes ACTIVE Enzymes P P cAMP ATP AMP

23. CAMP Pathway Activated adenylyl cyclase cAMP GTP P Signaling molecule ATP Activated G-protein subunit Phosphorylated protein ATP Activated G-protein dimer ADP Activated PKA Activated G-protein-coupled receptor (GPCR) Catalytic subunits Regulatory subunits Inactive PKA

24. Epinephrine as an example of cAMP pathway Epinephrine Skeletal muscle cell or Liver cell Activated adenylyl cyclase Activated GPCR GTP Activated G-protein  subunit ATP cAMP PKA (inactive) PKA (active) Phosphorylase kinase (inactive) Phosphorylase kinase (active) Glycogen synthase (active) Glycogen Synthase (inactive) P P ATP ATP ATP Glycogen phosphorylase (inactive) Glycogen phosphorylase (active) P Glycogen breakdown is stimulated. Glycogen synthesis is inhibited.

25. γ β O H2C (CH2)14 C CH3 OP O OH OH OH HC C (CH2)14 CH3 OP H+ O– H2C OH O P O O– H+ G-Proteins with cyclic DAG and IP3 Catecholamine, Peptide, or Protein • Hormone  Receptor  G-protein  Phospholipace-C • Phospholipase-C splits a special membrane phospholipid called PIP2 (phosphoinisitol 4,5 diphosphate) in two: • IP3 (Inisitol 1,4,5 Triphosphate) • DAG (Diacylglycerol) • 3a) IP3 binds to ligand gated channels releasing Ca2+; Ca2+ activates Calmodulin • 3b) Protein Kinase C binds to DAG and Ca2+ and kinases effector enzymes. Phospholipase-C DAG PIP2 Protein Kinase-C α P GDP GPCR G-Protein GTP IP3 Calmodulin Ca2+ Ca2+ Ca2+ O Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ H2C (CH2)14 C CH3 Smooth ER O HC C (CH2)14 CH3 O– OP + H+ OH OH H2C O P O OH O– H+ PIP2 IP3 DAG OP

26. GPCR with PLC (Brooker Fig. 9.16) Membrane phospholipid with inositol head group DAG Activated PKC IP3 released into cytosol ADP GTP ATP Protein that causes a cellular response Activated phospholipase C IP3 Signaling molecule Activated G-protein  subunit Ca2+ Activated calmodulin Activated G-protein- coupled receptor (GPCR) Endoplasmic reticulum

27. OH CH2 CH2 H2N H2N COOH COOH P O H+ H+ P O– O– O ATP ADP Tyrosine Phospho-Tyrosine Receptor Tyrosine Kinase Catecholamine, Peptide, or Protein • Hormone Binds to Receptor causing two subunits to come together • Each subunits Kinases (adds a phosphate to) Tyrosine residues on the other subunit • The receptor activates other proteins, often in a “Protein Kinase Cascade” • RTK activated proteins often act as transcription factors, moving into the nucleus to initiate transcription, but some (insulin for example) may have non-trophic responses • Mitogen-Activated-Protein Kinases (MAP-kinases) are often involved in cell division P P P Inactive Protein P mRNA Gene

28. KEY Signaling molecules Receptor Relay proteins Protein kinases Transcription factors Newly made proteins P Translation P P EGF molecules mRNA EGF receptor subunit P P P P Newly made proteins involved with cell division P Relay proteins Fos Grb Myc Sos GDP Ras Erk P P Ras GTP P Erk P Ras Mek Mek GDP Raf GTP Raf Raf Protein kinase cascade

29. Ligand Gated Ion Channels Na+ Na+ Na+ • Ligand Gated Ion Channels are comprised of 5 subunits, each being a 4-pass trans-membrane protein • Binding of a ligand (e.g. neurotransmitter) causes a conformational change that allows ions to flow down their concentration gradient. • Once inside the cell, the ions brings about intracellular responses. Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Gene

30. ADP ATP Steroid and Thyroid Hormone Receptors • Steroids and Thyroid Hormones are Trophic hormones (but not the only ones) • Entering the Cell • Steroid Hormones are Lipophilic and pass freely through the plasma membrane • Thyroid Hormones are actively brought across the cell by transport proteins at the expense of ATP. • Once in the cell both classes of hormones bind to and activate transcription factors resulting in Gene Transcription Steroid or Thyroid Hormone mRNA Gene