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39 Cards in this Set
- Front
- Back
What are the different types of chemical signals?
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Ligand - substance that binds to specific receptor initiating a particular event
Primary Messenger - ligand is example Second Messnger - transmit signlas from extracellular signaling ligands to cell interior (ex. cAMP, Ca2+, Inositol triphosphate, diacylglycerol) Messenger molecules include AA, Ach, peptides, steroid hormones, retinoids, nucleotides hydrophilic ligands bind to exterior, hydrophobic on nucleus or cytosol first message - ligand binds to signal second message - what happens inside |
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What are some characteristics of Signal Transduction?
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definition:
-detection of signal on cell surface and mechanism by which signal is transmitted into cell's interior, resulting in changes in cell behavior and gene expression Properties: -because they bind and release like enzymes they have kinetics, Km -for lipid soluble, receptor in cytosol or nucleus |
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What are factors that affect the interactions between ligands and their receptors?
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Receptor Affinity:
-high affinity = low conc. of ligand (called 'potency' in drug companies) Cognate receptor - receptor for specific ligand Dissociation constant (Kd) conc. of free ligand needed to produce 1/2 receptors occupied, small Kd = higher affinity between ligand and receptor receptor down regulation: -cell responds to high ligand conc. -removal of receptor for surface (internalization or tolerance) -raises Kd -tachyphylaxis - alters second messenger |
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What are some clinical features of Receptor Down-Regulation?
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Tolerance:
-prolonged use leads to loss of effectiveness due to receptor down-regulation ex. prolonged use of neosynephrine, which stimulates alpha-adrenergic receptors, causing blood vessels in nose to constrict to relieve sinus congestion Tachyphylaxis: -occurs on first dose ex. nitroglycerin as vasodilator to treat heart, vasoconstriction action of topical steroids on skin, not as effective second time. |
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What is the sequence of the Signaling Pathway?
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Reception:
Binding of epinephrine to G protein-linked receptor Transduction: 1. Inactive G protein --> Active G Protein 2. Inactive adenylyl cyclase --> active adenylyl cyclase 3. ATP --> cAMP 4. Inactive protein kinase A --> active protein kinase A 5. Inactive Phosphorylase kinase --> active phosphorylase kinase 6. Inactive glycogen phosphorylase --> active glycogen phosphorylase 7. Glycogen --> Glucose 1 Phosphate |
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What are some types of receptors?
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Ligand-gated channels - ionotropic
Intracellular recptors Second Messenger receptors - metabotropic |
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What is the structure of GPCRs?
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G Protein Copuled Receptors
Seven-membrane spanning receptors N-terminus: extracellular C-terminus: cytosolic (intracellular) G-protein interacts at cytosolic loop between 5th and 6th transmembrane helices 2 classes of G Proteins: Large heterotrimeric G-proteins: -alpha, beta, gamma -mediates signal transduction (Ga binds GTP, Gbg activates other 2nd messengers or channels) -Gs (stimulators) and Gi (inhibitors) -Ga exchanges GDP for GTP and dissociates from Gbg when ligand interacts with receptor Small Monomeric G Proteins: Ex. Ras |
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What are the different Heterotrimeric G Proteins?
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Gs:
Function - stimulates adenylate cyclase --> formation of cAMP Result - activation of protein kinases, ie. PKA Examples - binding of epi to BETA adrenergic receptors increasing cAMP levels in cytosol Gi: Function - inhibits adenylate cyclase preventing formation of cAMP Result - Protein kinases remain inactive Examples - binding of epi to ALPHA adrenergic receptors decreasing cAMP levels in cytosol Gq (Gp): Function - activates Phospholipase C (PLC), leading to formation of Inositol triphosphate (IP3) and diacylglycerol (DAG) Result - Influx of Ca into cytosol and activation of protein kinase C Examples - binding of antigen to membrane bound IgE causing release of histamine by mast cells |
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What is the G Protein Activation/Inactivation Cycle?
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1. Ligand binds to receptor
2. G-alpha releases GDP and binds GTP, activating G protein 3. Subunits separate 4. G Protein subunits activate or inhibit target proteins (this is the difference between Gs and Gi) 5. G alpha subunit hydrolyzes its bound GTP to GDP and becomes inactive 6. Subunits recombine to form inactive G protein |
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How is cAMP formed/degraded? What is its importance?
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Formed:
-Adenylate cyclase forms cAMP from cytosolic ATP Degraded: -Phosphodiesterase Target: -PKA, adds P to serine/threonine; regulatory subunits dissociate when cAMP binds to PKA cAMP pathways important in: 1 - glycogen metabolism 2 - heart contraction 3 - blood clotting 4 - secretion of salt and water in gut methylxanthines (caffeine and theophylline) and viagra are phosphodiesterase inhibitors NO released by neurons of penis cause dilation responsible for erection. Viagra helps maintain elevated cGMP in erectile tissue |
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What are some diseases results from disruption of G-protein signaling?
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Cholera toxin poisoning:
-Increase cAMP -alters salt secretion in intestine -chemically modifies Gs so that it can no longer hydrolyze GTP -vibrin cholera bacteria secrete toxin -water follows salt leading to severe dehydration Whooping cough (pertussis toxin) -increase cAMP -B. Pertussis - Gi is inactivated by pertussis toxin; Gi can no longer inhibit adenylate cyclase |
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What is the Inositol-phospholipid-calcium pathway?
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Gq uses IP3 and DAG as second messengers
Pathway: 1. Ligand binds to Gq-linked receptor 2. Gq is activated 3. Gq activates PLC-Beta 4. PIP2 is cleaves to IP3 and DAG 5. IP3 binds to IP3 receptor in ER 6. Calcium is released into cytosol and binds calmodulin 7. DAG activates protein kinase C (PKC) 8. PKC stimulates other pathways |
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How is Calcium important in signaling?
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Ca pumps keep Ca conc. low in cytoplasm
Ca ionophores: -A23187: antibiotic against gram positive bacteria and fungi, mobile Ca carrier Fura-2 a flouroescent dye binds to calcium and can use this dye for experiment calcium-calmodulin complex: -in cytosol Ca binds and activates calmodulin which target and regulate kinases and phosphatases |
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What is the pathway for the action of NO on blood vessel?
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1. G-linked receptor (Ach) --> InsP3
2. InsP3 --> Ca 3. Ca activates Calmodulin 4. Calmodulin goes to NO synthase 5. NO synthase creates NO 6. NO activates Guanylyl cyclase 7. Guanylyl cyclase goes to cGMP 8. cGMP activates Protein kinase G causes muscle relaxation (dilation of blood vessels) |
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What are Protein Kinase-Associated Receptors?
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Receptor Tyrosine Kinases RTK aggregate and undergo autophosphorylation
structure of tyrosine kinases: -single pass -tyrosines on cytosolic tail of receptor activation: -regulatory proteins with SH2 domains recognize and bind to phosphorylated tyrosines on receptor -this binding stimulates regulatory proteins |
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What is the RAS pathway?
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Activation:
-GRB2 (contains SH2 domain) interacts with phosphorylated receptor -Sos is associated with GRB2 and becomes activated -Sos (Son of Sevens) stimulates Ras to release GDP and bind GTP, Ras now active -Ras activates mitogen-activated protein kinases (MAPK) -MAPK phosphorylates transcription factors (AP-1) MAP kinases respond to extracellular stimuli (mitogens) and regulate gene expression, mitosis, cell survival/apoptosis Ras is inactivated by GTPase activating protein (GAP) |
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What are Oncogenes?
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proteins that ac as growth factors (EGF) , growth factor receptors (ErbB) and intracellular signaling molecules (Ras and Raf)
ERK MAP kinase lead to induction of genes that encode potentially oncogenic transcriptional regulatory proteins |
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What are mermbers of the Ras superfamily?
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Ras - cell proliferation
Rho - cytoskeletal dynamics/morphology Rab - membrane trafficking Rap - vesicular transport Arf - vesicular transport Ran - nuclear transport Miro - mitochondrial transport |
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What are the different growth factors?
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Epidermal growth factor (EGF):
target = epithelial and mesenchymal cells receptor complex = tyrosine kinase Transforming growth factor - alpha (TGFa): Target = same as EGF Receptor = same as EGF Platelet-derived growth factor (PDGF): Target = mesenchyme, smooth muscle, trophoblast Receptor = tyrosine kinase Transforming growth factor-Beta (TGFb): Target = fibroblastic cells, involved in cell-cycle regulation Receptor = serine-threonine kinase Fibroblast growth factor (FGF): Target = mesenchyme, fibroblasts receptors = Tyrosine kinase IL-2: Target = cytotoxic T lymphocytes receptors = 3 subunits Colony stimulation Factor 1 (CSF-1): Target = macrophage precursor Receptor = tyrosine kinase Wnts: Target = many embryonic cells Receptor = Seven-pass protein |
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What is dominant negative mutation?
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one polypeptide chain in protein disrupts function even though other ones are normal
disruption of growth factor through tyrosine kinase is example |
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What is Achondroplasia?
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dwarfism that results from autosomal dominant negative mutation of FGFR-3 gene
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What are some disruptions of growth factor?
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EGF:
-breast cancer, glioblastoma, fibrosarcoma TGF beta 1 - 1/3 ovarian cancers TGF beta 2 - colorectal cancer Smad4 - pancreatic cancers |
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What do Adrenergic receptors do?
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alpha receptors:
-bind both hormones -interact with Gq proteins (phospholipase C activation) -shuts down blood flow beta-adrenergic receptors: -binds epinephrine -interacts with Gs proteins (adenylate cyclase activation) |
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What are examples of cell function regulated by cAMP?
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Epinephrine:
function1 - glycogen degradation target tissue1 - muscle, liver function2 - FA production target tissue2 - adipose function3 - heart rate, BP target tissue3 - CV ADH: Function - water reabsorption Tissue - Kidney PTH: Function - bone resorption Target tissue - bone |
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How is Glycogen degradation controlled?
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1. Epi binds to Beta-adrenergic receptor
2. Gs alpha binds GTP, dissociates from Beta and Gamma 3. Activated Gs alpha activates adenylate cyclase 4. Adenylate cyclase produces cAMP from ATP 5. PKA binds cAMP and beocomes activated 6. PKA phosphorylates and actiaves Phosphorylase kinase 7. Phosphorylase kinase phosphorylates b into active a form 8. glycogen is cleaved into glucose-1-phosphate |
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What is Cyclic-AMP inducible gene expression?
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protein kinase A translocates to nucleus and phosphorylates transcription factor CREB leading to expression of cAMP-inducible genes
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How are alpha adrenergic receptors and Inositol-phospholipid-calcium pathway related?
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Alpha1 adrenergic receptors cause InsP3 pathway to release calcium via Gq
elevated calcium causes smooth muscle contraction and constriction of blood vessels opposite from beta adrenergic |
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Where are alpha and beta adernergic receptors located?
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alpha - surround peripheral veins and constrict
beta - around heart and bronchioles blood vessels and relax |
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What are good examples of Paracrine regulation?
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Histamine:
-IgE mast cells stimulate increase of Ca which induces secretion of histamine -causes allergy locally Prostaglandins: -typically active G protein receptor -aspirin reduces blood clots by blocking COX inhibiting prostaglandins from arachidonic acid |
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What are the two types of cell death?
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Necrosis:
-severe destruction along with inflammatory response (heterophagy) -hypoxia, toxins Apoptosis: -programmed cell death -usually at single cell level -autophagy - NO inflammatory response -physiologic or pathologic -helps prevent tumor growth, maintains immune system |
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What are the stages of Apoptosis?
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-DNA segregates to nuclear periphery
-cell produces organelle fragments -DNAses digest chromatin (shrinkage of cytoplasm) -cell fragmentation -cell is dismantled in apoptotic bodies |
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What are the different mechanisms for proteins during apoptosis?
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Protein cross-linking:
-mediated by transglutaminase Protein cleavage (fragmentation): -mediated by Caspases -laddering effect Loss of membrane asymmetry: -phosphotidylserine |
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What are caspases?
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zymogens
inactive until apoptotic signal activates one which cause a cascade leading to activation of others 3 classes: Initiator (caspases 8,9) Effector (executioner) - 3 Inflammatory response |
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What are the major Caspase-dependant apoptotic routes?
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Death receptor pathway:
-Fas ligand-Fas receptor -TNF Mitochondrial pathway (death-receptor independant): -innate -cyt c (stops ATP production) |
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What is Fas Signaling?
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recruit FADD
FADD recruits procaspase-8 (activates by self-cleavage) Caspase 8 activates Caspase 3 |
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How is Apoptosis triggered by DNA damage?
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p53 activates production of BAX
Bax interacts with mitochondria cytc recruits procaspase 9 caspase 9 stimulates caspase 3 |
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What are some factors released by mitochondria?
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Calcium:
-activation of caspases associated with ER Apoptosis Induced Factor (AIF): -stimulates large DNA fragmentation and condensation of chromatin Endonuclease G: -directly mediates nuclear DNA fragmentation |
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What is Cytolytic Granule-mediated Apoptosis?
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can circumvent requirement of FAS or TNF receptors
granzymes or NK cells activate effector caspases inside virus-infected cells also target: -Lamins -Histones -Mcl-1 (leads to activation of mitochondrial apoptotic pathway |
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What are Cancers caused by Apoptosis?
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Follicular B-cell Lymphoma:
-chromosomal translocation leads to up-regulation of Bcl-2 Melanoma: associated with Apaf-1 Autoimmune lymphoproliferative syndrome (ALPS): -mutation in Fas ligand or receptor |