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Endocrinology

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Published in: Biology
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Endocrinology

Subhamoy M / Kolkata

10 years of teaching experience

Qualification: M.Sc (Presidency College - 2011), B.Sc (Surendranath College - 2009), B.Ed (WBUTTEPA - 2019)

Teaches: Biology, Botany, Physiology, Zoology, Bio-medical, Food & Nutrition, Medical Entrance Exams, NEET

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  1. Signal Transduction Signal transduction at the cellular level refers to the movement of signals from outside the cell to inside. Or It is the biochemical manner in which the cell (in response to external stimuli) converts signals into a cell response. Examples are: Threat -5 epinephrine (adrenaline) released from adrenal glands -Y binds to ß-Adrenergic receptor of a cell -5 energy stores are mobilized and cardiac function is improved. Intake of full meal insulin released from ß-cells of Pancreas binds to Insulin receptor -5 increased glucose uptake. Wound Epidermal growth factor (EGF) released stimulates specific cells to grow and divide (assists in expression of growth-promoting genes) In each case, the cell receives information that a certain molecule within its environment is present more than its normal concentration (i.e. greater than its threshold concentration). The chain of events which converts this information (signal) into a final physiological response is known as signal transduction.' The signal molecule (i.e. adrenaline, insulin or EGF) is known as the "primary messenger" or the "ligand". Signal transduction systems allow information to control cellular processes such as: Gene expression. Change in enzyme activity. Growth. Responses to stress. Death. Developmental changes. Adaptations. Locomotion. Signaling Molecules: Examples of signal molecules: Hormones. Growth factors. Extracellular matrix components e.g. fibronectin. Cytokines. Neurotransmitters e.g. acetylcholine. Basic Principles of Signal Transduction
  2. The coordination of metabolism in the separate organs of mammals is achieved by hormonal and neural signaling. Individual cells in one tissue sense a change in the organism's environment & respond by secreting extracellular chemical messenger. Endocrine cells secrete hormones, neural cells secrete neurotransmitters. The extracellular messenger passes to another cell binds to a specific receptor molecule triggers a change in the activity of the second cell. Chemical msn r Route Distance NEURAL SIGNALING Neurotransmitter (e : Acet Icholine) Thru blood to distant or ans & tissues Only a fraction of micrometer HORMONAL SIGNALING Hormones From one neuron to the next across thes a tic cleft May travel a meter before encounterin a tar et cell. During signal transduction: the number of proteins & other molecules participating in these events increases as the process goes from the initial stimulus, resulting in a signal cascade, eliciting a large response Elements of a signal transduction System Sender Signal Nondestructive Medium Selective Receiver Transducer Amplifier Effector Response Principles of Signal Transduction Environmental (Primary messenger) Cell surface receptor Signal Reception (Secondary messenger) Amplification Feedback pathways Regulate the entire signal process. Other chemical forms (Multi-step) Cellular effectors Transduction Response(s)
  3. Signal-transduction pathway: Signal transduction pathways allow cells to respond to environmental signals. 1. 2. 3. 4. 5. Release of primary messenger: a stimulus (wound/digested meal etc.) triggers release of signal molecule. Reception of primary messenger: Transmembrane receptors on cell membrane recognize and bind the primary messenger (or the ligand). The primary messenger binds to the extracellular half of the receptor -5 changes its tertiary or quaternary shape and conveys another signal (second messenger) inside the cell. Delivery of message inside the cell by the second messenger: small molecules called 2nd messengers convey signals received at receptors on the cell surface to target molecules in the cytosol or nucleus. These are intracellular molecules that change in conc. in response to environmental signals (i.e. primary messenger). Examples: cyclic AMP and cyclic GMP, calcium ion, inositol 1,4,5-triphosphate (IP2) and diacylglycerol (DAG). Activation of effectors that directly alter physiological response: the ultimate effect of the signal pathway is to activate/inhibit pumps, enzymes & gene-transcription factors that directly control metabolic pathways, gene activation, nerve transmission etc. Termination of the signal: after the response has been achieved, the signal must be terminated or else the cell will lose its responsiveness to new signals. If not terminated, signal-transduction processes can cause many cancers (especially processes that control cell growth). Second messengers: are molecules that relay information from the receptor-ligand complex. Second messengers have the following properties: a. b. c. d. e. They amplify the strength of the signal. Enzymes or membrane channels are activated in 2nd messenger generation. A low conc. of signal in the environment (may be a single molecule), can yield a large intracellular signal (i.e. large number of second messengers) and large response. They are often free to diffuse to other cellular compartments where they can influence processes throughout the cell Input from several signaling pathways at one time rather than signal from individual independent pathways (cross talk) may affect the conc. of common 2nd messengers. Cross-talk can either enhance the activity of the cell or cause the changes in 2nd messenger conc. to be misinterpreted. Mechanism of second messenger production (i.e. Step 2 and 3 of signal-transduction pathway):
  4. Hydrophilic messengers cannot cross the cell membrane. This restriction forces them to produce intracellular 2nd messengers. Ligand binds to receptors (located on the external surface of plasma membrane). The resultant ligand-receptor complex is coupled to an enzyme located on the internal surface of cell membrane & stimulates the conversion of some metabolite into a 2nd messenger. The 2nd messenger acts by stimulating or inhibiting protein phosphorylation/ dephosphorylation cascades. Cascades have advantages such as signal divergence, convergence & amplification. Two Features of transduction that alter protein shape and function: Allosteric changes Phosphorylation Many 2nd messengers produce responses by binding to & activating protein kinases, ion channels etc to continue the signaling cascade. Protein kinases: Enzymes that transfer the terminal phosphate of ATP to specific serine, threonine, or tyrosine residues in proteins. OH (Ser, T hr, Tyr) ATP (Ser. Thr, T yr) ADP Protein phosphatases: Enzymes that hydrolytically remove specific phosphoryl groups from modified proteins. They are one mechanism for the termination of a signaling process. Types of receptors I- Cell-surface receptors II- Internal receptors Cell-surface receptors: Most signal molecules are too large & too polar to pass thru the membrane. Membrane associated receptor proteins perform the function of information transfer across the membrane without the ligand itself passing thru the membrane. They allow the activation of signal transduction pathways in response to activation by the ligand. E.g.: seven-transmembrane-helix receptors (7 TM receptors), they change conformation in response to ligand-binding and activate G-proteins
  5. Cell-surface receptors may be: 1- 2- Integral transmembrane receptors Recognize vast majority of extracellular signaling molecules. Usually for proteins & charged molecules They give rapid response, seconds - minutes Example; receptors for epinephrine and growth hormone. Transmembrane receptors: Span the plasma membrane of the cell, with one part of the receptor on the outside of the cell (extracellular domain) and the other on the inside of the cell (intracellular origin). Eg: G-protein coupled receptors: Receptor tyrosine kinase. Transmembrane receptors E=extracellular space IP=plasma membrane l=intracellular space Biological functions mediated by 7 TM receptors Smell Taste Vision Neurotransmission Hormone secretion Chemotaxis Exocytosis Control of blood pressure Embryogenesis Cell growth and differentiation Development Viral infection Carcinogenesis
  6. About 7 TM receptors: (also called as serpentine receptors) They are the largest class of cell-surface receptors B-adrenergic receptor (ß-AR, for epinephrine) is of this class They are responsible for transmitting information initiated by signals as diverse as hormones, neurotransmitters, odorants, tastants & even photons. Approx. 50% of therapeutic drugs use target receptors of this class. These receptors contain seven helices that span the membrane bilayer. First member of this family to have its 3D structure determined was rhodopsin, which plays an essential role in vision. Binding of a ligand from outside the cell to 7 TM receptor induces a conformational change in the part of the receptor inside the cell. This conformational change in the receptor's cytoplasmic domain activates a protein called a G-protein. The activated G protein stimulates the activity of adenylate cyclase. The G protein & adenylate cyclase remain attached to the membrane, whereas cAMP can travel throughout the cell carrying the signal originally brought by the binding of the ligand. Adenylate cyclase: an enzyme that increases the conc. of cAMP by forming it from ATP. G proteins are so-called because they bind the guanine nucleotides GDP and GTP. They are heterotrimers (i.e., made of three different subunits) associated with the inner surface of the plasma membrane and transmembrane receptors of hormones, etc. These are 7 TM receptors called G protein- coupled receptors (GPCRs) because they signal through G-proteins The three subunits are: Ga -Y carries the binding site for the nucleotide (GDP or GTP). At least 20 different kinds of Gu molecules are found in mammalian cells. The u and y subunits are anchored to the membrane by covalently attached fatty acids. Hormone-bound receptor -5 catalyzes the exchange of GTP for bound GDP. How They Work: • In the inactive state, Gu has GDP in its binding site. When a hormone/ligand binds to the associated GPCR, an allosteric change takes place in the receptor (its tertiary structure changes). This triggers an allosteric change in Gu causing GDP to be replaced by GTP. GTP activates Gu causing it to dissociate from Gß, Gy (which remain linked as a dimer). Activated Gu in turn activates an effector molecule.
  7. Eg: the effector molecule is adenylyl cyclase - an enzyme in the inner face of the plasma membrane which catalyzes the conversion of ATP into the "second messenger" cyclic AMP (cAMP) Adenylate cyclase bound to Gus bound to GTP nATP > ncAMP (G proteins transmit a signal when bound to GTP and they are silent when bound to GDP) "OFF' GOP position H 20 GTP position GOP The dissociation of the G-protein heterotrimer into Gu and Gßy units transmits the signal that the receptor has bound its ligand. A single hormone-receptor complex can stimulate nucleotide exchange in many G-protein heterotrimers. Thus, hundreds of Gu molecules are converted from their GDP into their GTP forms for each bound molecule of hormone, giving an amplified response. Switching off of the signal initiated by Epinephrine Gu subunits have intrinsic GTPase acitivty which is used to hydrolyze bound GTP into GDP & Pi. This hydrolysis rxn is slow, so activated Gu is able to activate the downstream components before its hydrolysis. This conversion, along with the return of Gß and Gy subunits, restores the G protein to its inactive state. GS with GDP bound is turned off; it cannot activate adenylate cyclase. Contact of GS with hormone— receptor complex causes displacen.ent of bound GDP by GTP. GTP GDP" GS with GTP bound is turned on; it can activate adenylate cyclase. The B, y subunits dissociate from a. GDP GTP GDP GTP bound to GS is hydrolyzed by the intrinsic GTPase at GSC* ; GSO thereby turns itself "off." The inactive a subunit reassociates with the p, y subunits.
  8. Epinephrine binding to the ß-adrenergic receptor activates cAMP-dependent protein kinase Epinephrine binds to a specific receptor. Rec The occupied receptor causes replacernent of the GDP bound to GS by GTP, activating Gs. AC GDP GTP GDP GS (a subunit) rnoves to adenylate cyclase and activates it. cANIP-dependent protein kinase (protein kinase A) is activated by cANIP. Phosphorylation of cellular proteins by protein kinase causes the cellular response to epinephrine. GTP ATP Adenylate cyclase catalyzes the forrnation of 3' ,5'- cyclic AMP. cAMP cvclic nucleotide phosphodiesterase 5' -AMP Cyclic nucleotide phosphodiesterase degrades cAMP, reversing the activation of protein kinase A. The net result of binding of Epinephrine to the cell surface receptor increased production of cAMP inside the cell. By binding of Epinephrine, cAMP exhibits different effects in different tissues. *In the muscle stimulates the production of ATP for contraction. *In other cells Enhances degradation of storage fuels Increases the secretion of acid by the gastric mucosa. Leads to dispersion of melanin pigment granules. Diminishes aggregation of blood platelets. Induces the opening of chloride channels.
  9. Protein kinase A (PKA) Most effects of cAMP in eukaryotic cells are mediated by the activation of a single key enzyme protein kinase A (PKA) PKA consists of two regulatory (R) chains & two catalytic (C) chains. In the absence of cAMP, the R2C2 complex is inactive. Binding of cAMP to the regulatory chains releases the catalytic chains which become catalytically active. Activated PKA then phosphorylates specific serine & threonine residues in many targets to alter their activity. Cartoon of cAMP-dependent protein kinase Inactive Regulatory subunits: empty cAMP sites Catalytic subunits: substrate binding sites blocked by autoinhibitory domains of R subunits Regulatory subunits: autoinhibitory domains buried Active Catalytic subunits: open substrate binding sites c 4 cAMP c c 4 cAMP c Resetting of the hormone bound activated receptor It should be reset to prevent continuous activation of G proteins. It is done by 2 processes: 1) The hormone dissociates returning the receptor to its initial inactivated state. The receptor remains in its unbound state depending upon the conc. of the hormone. 2) Deactivation by phosphorylation of serine & threonine residues in the carboxyl-terminal tail of the hormone-receptor complex. For eg: ß-adrenergic receptor kinase (also called G- protein receptor kinase 2, GRK2) phosphorylates the hormone receptor complex. Finally, arrestin binds to the phosphorylated receptor & further diminishes its ability to activate G proteins.
  10. Some Hormones Act by Inhibiting Adenyl Cyclase E.G. Somatostatins, that counter act the action of glucagon. Prostaglandin E2 (PGE2), that counter act the action of epinephrin in adipose tissue. In other tissues PGE2 activates adenyle cyclase. So, extracellular signal may have different effects on different tissues according to: 1 -Type of receptor. 2-Type of G-protein 3- Set of enzymes suseseptable for phosphrylation by cAMP dependent protein kinase. Examples ofA enzymes regulated by cABIP-dependent phosphorylation Effect Enzyme Glycogen synthase Phosphorylase kinase Acetyl COA carboxylase Pyruvate dehydrogenase complex Hormone sensitive lipase PFK2/Fructose bis-phosphatase Pathway glycogen synthesis glycogen breakdown fatty acid synthesis Pyruvate to acetyl- COA triacylglycerol mobiliz ation/ fatty acid oxidation glycolysis/ gluconeogenesis G proteins both activate and inhibit adenylate cyclase
  11. Stimulatory external signal sa 7 GDP Inhibitory external signal Plasma Cytosol GTP GDP 7 H20 G,a.GDP Caffeine. Cholera ia 7 H20 Gia.GDP ATP ADP Y ia GDP GTP Pertussis theophyltine toxin 4AMP Phosphodiesterase 4 ATP 4cAMP + R2C2 toxin Protein (inactive) Protein. (active) Cellular response phosphoprotein phosphatase H20 4H20 G-protein families and their functions Ga class Initiatin si nal G as Gai Gat G a 13 ß-Adrenergic amines gl ucagon, parathyroid hormone, many others Acetylcholine, ct -adrenergic amines, ma ny neu rotransmitters Photons Acetylcholine, a -adrenergic amines intracellular calcium, many neurotransmitters Thrombin, other agonists Downstream si nal Stimulates adenylate cyclase Inhibits adenylate cyclase Stimulates cGMP p hosp hod i estera se Increases IP3 and Diacylglycerol Stimulates Na+ and H+ exchange Examples Of Adenylate Cyclase Cascades
  12. 1. In glycogen metabolism, it modulates enzyme activity PKA phosphorylates two enzymes - glycogen phosphorylase, causing glycogen breakdown. - glycogen synthase, causing inhibition of further glycogen synthesis. 2. PKA stimulates the expression of specific genes by phosphorylating a transcriptional activator called (the cAMP response element binding (CREB) protein). This activity of PKA illustrates that signal-transduction pathways can extend into the nucleus to alter gene expression. 3. Serotonin binds to a 7 TM receptor to trigger an adenylate cyclase cascade. -The rise in cAMP level activates PKA, which facilitates the closing of K+ channels by phosphorylating them. - Closure of K+ channels increases the excitability of the target cell. Thus, signal-transduction pathways that include 7 TM receptors, can result in the modulation of membrane excitability. Phosphoinositide Cascade Vasopressin binding to a 7 TM receptor (angiotensin Il receptor) This activates Gaq that subsequently activates the ß- isoform of the enzyme phospholipase C. The activated enzyme then hydrolyzes phosphatidyl inositol 4,5 diphosphate (PIP2). producing two 2nd messengers: - inositol 1,4,5-trisphosphate (IP3), a soluble molecule that can diffuse away from the membrane. (to the cell 's interior) - diacylglycerol (DAG), which stays in the membrane (hydrophobic) o 1 o H 20 CH20 CH*OH. (DAG) 1 Ho HO HO OH 00 PhosphetIdylInosJtol (PIPa) OH Ines/t08 1.4.5-tncpho•phate Unset) during the activation of adenyiate cyclase, However, this G protein activates a dif- ferent membrane-bound enzyme, a phosßholipase C, which in turn cleaves PIPa to yield two products (step (DAG) and inositoi trisphosphate (InsPJ). * IP3 causes the rapid release of Ca2+ from intracellular stores in the endoplasmic reticulum &, (in smooth muscle cells, the sarcoplasmic reticulum). It binds with a membrane protein called the IP3-gated channel or IP3 receptor.
  13. * At least three molecules of IP3 must bind to sites on the cytosolic side of the membrane protein to open the channel and release Ca2+. *Binding of IP3 to IP3 receptors causes them to open & allows inflow of Ca2+ ions from the ER into the cytoplasm. *The elevated level of Ca2+ in the cytosol then triggers processes such as smooth muscle contraction, glycogen breakdown, and vesicle release. *Ca2+ ions is itself a signaling molecule: it can bind proteins such as calmodulin. *Ca2+ also facilitates the activation of enzyme protein kinase C. DAG remains in the plasma membrane where it activates protein kinase C. Protein kinase C phosphorylates serine & threonine residues in many target proteins. The specialized DAG-binding domains of protein kinase C requires bound Ca2+ to bind to DAG. - Inositol 1,4,5-trisphosphate is short-lived (lifetime is less than a few seconds). - Inositol 1,4,5-trisphosphate can be degraded to inositol by the sequential action of phosphatases, or - It can be phosphorylated to inositol 1,3,4,5-tetraphosphate, which is then converted into inositol by an alternative route. Lithium ion, widely used to treat bipolar affective disorder, may act by inhibiting the recycling of inositol 1,3,4-trisphosphate. Metabolism of IP3. The IP3 signal is terminated by its metabolism by Inositol polyphosphate phosphatases. 2- OP032 OH H OH OP03 (3 steps) OH OH H OH H OH O OP032 OH OH inositol
  14. OH 2-03 I nesitol OH PO/ PO.32- OH OH P032- poe- 2-0 3 OP03?- 2-03 pod pos?- linesiiel 1 i3i4.i'isphesphat• OH How is the diacylglycerol-initiated signal turned off? Metabolism of Diacylglycerol. Occurs by: (1) phosphorylation to phosphatidate or (2) hydrolysis to glycerol and fatty acids. Protein Kinase C Activation by Diacylglycerol. - When the Cl domains bind to diacylglycerol in the membrane, the pseudosubstrate is pulled from the active site, permitting catalysis. - Calcium-binding C2 domains help to localize P KC to the membrane.
  15. Pseudosubstrate binding at active site Inactive protein kinase C in solution Activated protein kinase C bound to membrane CIA CIB Diacylglycerol Exampls for signals that activate Gaq - Acetylcholine, - a-adrenergic amines. - Vasopressin on hepatocytes - Thyrotropin releasing hormone on pituitary Calcium ion Ca2+ is an important component of the phosphoinositide cascade The cytosolic level of Ca2+ in unexcited cells is typically 100 nM (0.1 mM) , Several times lower than the concentration in the blood, which is approximately (2.12 to 2.62 Calcium is kept low intracellular because if its level increases, it complexes with phosphorylated and carboxylated compounds forming insoluble compounds. How Calcium is kept low intracellular? In eukaryotic cells, this is done by: the Ca2+ ATPase, that pumps Ca++ from the cytosol to the ER. the sodium-calcium exchanger, that pumps Ca++ out of the cell. IP3 activates Ca++-release channels in ER membranes. Ca++ stored in the ER is released to the cytosol, where it may bind calmodulin, or help activate Protein Kinase C. Signal turn-off includes removal of Ca++ from the cytosol via Ca++-ATPase pumps, & degradation of IP3. Ca++ calmodulin IP3 Ca++-release channel endoplasmic reticulum ATP ADP + PI Ca
  16. Calcium Activates Calmodulin, Which Stimulates Many Enzymes and Transporters Ca++ triggers cellular responses by activating several enzymes including Ca++- dependant PK. The regulatory subunit of this enz is a Ca++-binding protein (Calmodulin). t Intracellular Ca++ Ca++ binding to 4 high affinity sites in calmodulin conformational changes -5 association of calmodulin to several proteins modulating their activity. • cAMP phosphodiesterase is a Ca++/calmodulin-dependent enz, So, tCa++ -Y UcAMP (CROSS TALK) Mode of Binding of Ca2+ to Calmodulin. Calcium is coordinated to six oxygen atoms from the protein and one of water. The role of PIP2 in intracellular signaling External 1 signal Protein khase 2 GTP GDP H20 GDP Protein (inactive) 6 Cellular Protein• response ATP (active) 4 ADP Ca2•-.--.-..+ 5 5 Protein (inactive) ADP ATP IP2 Inositol trisphosphatase IP3 Endoplasmic reticulum IPg—gated Ca transport channel Receptor Tyrosine kinase-based signaling Receptor tyrosine kinases 50 different transmembrane glycoproteins Ca Ligands bind to the extracellular domains of transmembrane receptors that have tyrosine kinase domains present within their intracellular domains. Typically ligand causes receptor autophosphorylation on activation loops
  17. Examples (Growth factors) - insulin, - epidermal growth factor (EGF) platelet-derived growth factor Epidermal growth factor (EGF) A single polypeptide chain consisting of 1186 residues The receptor tyrosine kinase is monomeric and enzymatically inactive in the absence of the growth factor. The binding of EGF to the extracellular domain causes the receptor to dimerize and undergo cross-phosphorylation and activation. Endocytosis of receptor-hormone complexes or degradation in lysosomes is the principal way the number of receptors on the surface of cells are reduced and thus reduction of the sensitivity. Binding of Growth Hormone Leads to Receptor Dimerization (A) A single growth-hormone molecule (yellow) interacts with the extracellular domain of two receptors (red and orange). (B) The binding of one hormone molecule to two receptors leads to the formation of a receptor dimer. Dimerization is a key step in this signal-transduction pathway. hormone domain her intracellular domain Oimerized receptor (activated) receptor (extracellular domain) - The binding of growth hormone to its receptor leads to receptor dimerization, which brings two Janus kinases (JAKs) together in such a way that each phosphorylates key residues on the other. - The activated JAKs remain bound to the receptor. H o r m one-induced d irnerization Cross- phos ati on Act OAK
  18. Insulin receptor is a receptor tyrosine kinase Immunoglobin-like domain Cysteine- rich domain s-s s-s Extracellular medium Plasma membrane Cytosol Tyrosine kinase domain Kinase sequence EGF receptor PDGF NGF receptor receptor Insulin receptor IGF-I receptor Insulin receptor is a receptor tyrosine kinase The insulin receptor is a disulfide-bonded dimer of u-ß pairs even when insulin is not bound. insulin is required for the activation of the kinase, demonstrating that dimerization is necessary but not sufficient for activation. The binding of the growth factor *conformation changes in the subunits of the dimer brings appropriate tyrosine residues from one chain into the active site of the other chain cross-phosphorylation (auto-phosphorylation). Structure of insulin receptors a subunit (hormone-binding domains) subunit (ATP-binding and tyrosine kinase domains) How is the signal transferred beyond the receptor tyrosine kinase? The activated receptors phosphorylate other proteinscalled Insulin Receptor Substrates -IRS ( IRSI, IRO, IRs3 and IRS4 ) . .1RS act as "second messengers" of insulin
  19. The phosphorylation of the tyrosine residues in the RSS "attracts" proteins containing SH2 domains (domains that bind to phosphorylated tyrosine) activating them. Insulin Insulin receptor Cross- phosphorylation Activated receptor Enzymatic Amplification reaction Phosphorylated IRS proteins Protein—protein interaction Localized phosphoinositide 3-kinase Enzymatic Amplification reaction PhosphotidyIinositoI-3,4,5-trisphosphate (PIP3) Protein-lipid interaction Activated PIP3-dependent protein kinase Enzymatic Amplification reaction Activated Akt protein kinase Increased glucose transporter on cell surface Figure 14-24 Biochemistry, Sixth Edition 0 2007 W. H. Freeman and Company

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