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BICH 410: SIGNAL TRANSDUCTION
What are the first messengers |
Hormones
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What are examples of secondary messangers? |
cAMP, cGMP, Ca(+2), Inosityol 1,4,5 triphosphate TP3, and diacyglycerol (DAG) are examples
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Hormone |
provide a mechanism to maintain homeostasis, to respond to changing metabolic conditions and to regulate cellular differentiation and genetic expression
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3 types of hormones |
1. Amines- catecholamines- simple molecules that have NH2 groups at the end. (Epinephrine)
2. Proteins and peptides (peptide hormones) made from chains of amino acids (insulin, glucagons, and growth hormones) 3. Steroids- derived from cholesterol and regulate metabolism, electrolyte balance, inflammatory response and sexual function (made from lipids) basic sturcture made up of three 6-carbon rings and one 5carbon ring. (Testosterone and cortisol)
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3 Types of Receptors |
7-TMS receptor- integral membrate proteins with 7-tms transmembrane alpha helical segments (G-binding proteins)
1-TMS receptor- which are proteins that a single transmembrane alpha helix that spans the membrane (tyrosine kinases, guanylate kinases) Ogliomeric Ion Channels- consists of multiple protein subunits. These channels are also called ligant gated channels because the bind of the hormone to the receptor opens the ion channel
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G-Protein Coupled Receptors |
G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors (GPLR), comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses.
Also intermediaries in signal trans. from 7TMS receptors. binding sites for guanosine nucleotides. (Binary switches). Every 7TMS has a G-protein coupled. Hormone receptor mediate processes regulated by G-proteins may be stimulatory
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Agonists |
A ligand that can bind to a receptor, alter the function of the receptor and trigger a physiological response.
can be characterized by how much physiological response can be triggered, and the concentration of the agonist that is required
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Antagonist |
Ligands that bind to a receptor but fail to activate the physiological response
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Trimeric G-proteins |
Heliotrimers consisting of alpha, beta, and gamma subunits
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Quaternary Structure |
arrangement of multiple folded protein or coiling protein molecules in a multi-subunit complex. For nucleic acids, the term is less common, but can refer to the higher-level organization of DNA in chromatin,[7] including its interactions with histones, or to the interactions between separate RNA units in the ribosome[8][9] or spliceosome.
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Enzymatic activity of alpha subunit |
Diffuse laterally through the membrane until it associates with adenylate cyclase.
Once associated with adenylate cyclase, it activates it, and begins to produce cAMP in the resting state, GDP is bound and when it becomes activated, it releases GDP and binds GTP.
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Small G-proteins |
small proteins that bind guanosine nucleotides and have intrinsic GTPase activity.
Constitute a huge superfamily of proteins which include Ras
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Ras |
A small G-protein that stimulates cell growth and differentiation.
works alongside the epidermal growth factor (EGF) and is its receptor activate. With GTP bound it activates Raf kinase Bound by Sos, it starts a phosphorylation cascade leading to the phos. of MAPK--> activates kinase, migrates to nucleus and it phos. trascription factors regulation gene expression
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Protein Kinases |
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation).
-- usually serine, threonine and tyrosine residues
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Tyrosine Kinases |
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell.
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Adenylate Cyclase |
lyase enzyme that produced cAMP from ATP and is activated by the association of adenylate cyclase with G-proteins alpha subunit.
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Guanylate Cyclase |
also a Lyase enzyme, catalyzes GTP to cGMP
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phosphodiesterase |
Hydrolyzes phosphodiester bonds to convert cAMP to AMP
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Phospholipase C |
an effector protein-- when activated by a G-protein- it hydrolyzes phosphatidylinositol diphosphate
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Protein Kinase C |
Activated by DAG, this effector protein uses ATP and requires Ca(+2) which is induced to release by IP3 in the endoplasmic reticulum and the calciosomes- to phosphorylate serine and tyrosine residues of many target proteins
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Protein Kinase A |
Activity is dependent upon the level of cAMP, so when cAMP rises, cAMP binds to the two binding sites on the regulatory subunits which leads to release of the catalytic subunits. PKA directly can increase or decresase the activity of a protein.
In protein synth. PKA first directly activates CREB which binds the cAMP, altering the transcription and synthesis of protein.
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Calmodulin |
Intracellular calcium binding protein, binds 4 Ca(+2) and is bound by target proteins which activate Calmodulin.-- can fuel calmodulin dependent protein kinases
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Mitogen Activated Protein Kinases |
Mitogen-activated protein (MAP) kinases () are serine/threonine-specific protein kinases that respond to extracellular stimuli (mitogens, osmotic stress, heat shock and proinflammatory cytokines) and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.
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Mitogen Activated Protein |
activated by MEK, and can migrate from the cytosol to the nucleus where it phosphorylates transcription factorsthat induce the trans. of specific genes
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MAPKK |
is a kinase enzyme which phosphorylates mitogen-activated protein kinase. -- dual phosphorylation is facillitated by dual-specificity MAPKK and are activated by serine/threonine phosphorylation by MAPKKK
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MAPKKK |
activates MAPKK
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MEK |
Activated by Raf kinase, is then phosphorylated and can branch off to other effectors but also activates MAPK
MAP kinases are proline-directed serine/threonine kinases that are activated by dual phosphorylation in response to diverse extracellular stimuli Stimulated by growth and differential factors
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ERK |
Stimulated by MEK (which was stim by Raf) ERK integrats signals leading tot eh ligand and cell type-specific responses... also an MAPKKK
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IRS-1 |
Insulin receptor substrate 1 (IRS-1) is a protein that in humans is encoded by the IRS-1 gene.
When insulin binds to one or both of the insulin binding sites, the receptor undergoes conf. changes including cross phos. which activates the tyrosine kinase activity for other target proteins such as IRS-1 Target proteins-- IRS-1 Is associated with other effector proteins such as Grb2
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Raf-1 |
Raf-kinase activates MEK
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GRB |
Associated with IRS-1 and binds Sos
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Sos |
Activated & bound by Grb-2 and it binds and activates Ras
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STAT |
Signal transducers and activartors of transcription.
Has a high affinity for specific binding sites on DNA which regulate gene expression
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JAK |
Janus Kinase- tyrosine kinases- They cross posphorylate eachother which causes conformational changes that activate the two kinases for other protein substrates such as STAT
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Caffeine |
Inhibits phosphodiesterase (which hydorlyzes the phosphodiester to convert cAMP to AMP) thus increases the concentration of cAMP
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Sildenafil |
Viagra. it is a drug that inhibits cGMP specific phosphodiesterase type 5- an enzyme that regulates blood flow to the penis
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Secondary Messenger |
Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus.
on the inside of the cell and are able to send cytoplasmic responses into the cell mostly for nonseteroid hormones can diffuse to cellular compartments such as the nucleus where the second messanger influences gene expression. The signal carried by the hormone becomes amplified as one hormone bound to the receptor can instigate form. of 100s secondary messenger.
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Insulin |
Polypeptide hormone that regulates the carb and fat metabolism in the body. It is sythesised as proinsulin in the pancrease and then processed into insulin and is a free conecting poly peptide
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Under what conditions is insulin released into the blood stream? |
High blood glucose concentration which throws off the ATP/ADP balance which signals the insulin
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What type of receptor is the insulin receptor? |
Dimer of 2 1-TMS domains held together by disulfide bonds
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What happens when insulin binds to the receptor? |
Promotes transport of glucose, amino acids and fatty acids from blood into the liver, muscle and adipose. Promotes the storage of glucose into glycogen, protein and triglyceride for storage in the liver and the muscle tissue and also promotes protein biosynthesis and glycolysis
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What tissues contain insulin receptors? |
Liver (adipose, skeletal muscle)
NOT the eye, brain, heart or lungs
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Effects of insulin on these tissues |
Causes uptake of glucose
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What type of hormone is Glucagon |
Polypeptide
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What tissue produces glucagon? |
Pancreatic alpha cells
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Under what conditions is glucagon released in the blood stream? |
Low blood glucose, or high insulin levels as well as activity, stress, exercise, and high plasma levels of amino acids (which indicates a state of starvation
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What type of receptor is the glucagon receptor |
g-protein coupled receptor which increases cAMP and activates protein kinase A
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What happens when Glucagon binds to the receptor |
It releases cAMP and activates protein kinase A
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What tissues contain glucagon receptors |
Main site is the liver where it promotes glycogenolysis and gluconeogenesis.. it also promotes lipolysis in adipose tissues
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What are the effects of glucagon on these tissues? |
the liver and kidneys break down and degrade glucagon to degrade glycogen in roughly 6 minutes
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What type of hormone is Epinephrine? |
Caticholamine
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What tissue produces epinephrine |
Adrenal glands
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Under what condition is epinephrine released into the blood stream? |
all times but increased during times of stress
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What type of receptor are the beta-adrenergic receptors |
The resting G-protein is a heterotrimer consising of alpha, beta, and gamma subunit and it is STIMULATORY
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What type of receptor are the alpha-adrenergic receptors? |
Inhibitory
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What happens when Epinephrine binds to beta-adrenergic receptors? |
Induces a confomtaional change that is detected inside of the cell. The binding of epinephrine activates G-protein. The activated G-protein in turn activates Adenylyl cyclase which converts ATP to cAMP and pyrophosphate
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What happens when epinephrine binds to alpha-adrenergic receptors? |
Causes the exchange of GDP for GTP causing the G-alpha"i" subunit to dissociate from the G-beta-gamma dimer. and INHIBITS adenylate cyclase
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What tissues contain adrenergic receptors |
Heart, tear duct, bladder
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What are the effects of epinephrine on these tissues? |
increase or decrease in fuction
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Outline events that happen when Glucagon binds to its receptor? |
1. Alpha G- binds to GDP-- conformational change activated
2. Activates a G-protein trimer and GDP released, bind GTP to alpha subunit 3. alpha subunit dissociates from the dimer 4. alpha subunit diffuses laterally through the membrane until it associates with adenylate cyclase 5. G-protein activates adenylyl cyclase 6. adenylyl cyclase converts ATP into cAMP and pyrophosphatate
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Outline events when Epinephrine binds to the beta-andrenergic receptor |
1. Epinephrine binds to beta-and. located outside of the cell
2. induces a conf. change that is detected and activates a G-protein 3. G-protein causes the alpha subunit to release GDP and bind GTP 4. Alpha subunit dissociates from the G-beta-gamma dimmer 5. Alpha subunit diffuses laterally through the membrane until it associates with adenylate cyclase 6. G-protein activates adenyl cyclase 7. Adenyl cyclase converts ATP into cAMP and pyrophosphatate
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Outine events that occur in Phosphoionositide cascade |
1. Vasopressin is an antidiuretic hormone that binds to the vasopressin receptor (7TMS receptor)
2. binding of vasopressin induces associated G-protein to exchange GDP for GTP causing the alpha subunit to dissociate from the dimer. 3.Alpha sub with the GTP bound associates with phospholipase C activating the Lipase 4. Activated lipase hydrolyzes the phosphodester bond linking the phosphorylated inositol to the diacylglycerol 5. Cleavage produces 2 second messangers, IP3 and DAG 6a. DAG diffuses laterally in the lipid membrane and activates PKC. 6b. IP3 diffuses into the cytosol and promotes a fast release of Ca2+
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Sequence of events that occur when insulin binds to its receptor |
1. insulin binds and receptor undergoes autophosphorylation
2. insulin receptor phosphorylates IRS-1 on its tryosine residues 3. SH2 domain of Grb2 binds to P-tyr of IRS-1, Sos binds Grb-2->Ras, causing GDP to release and GTP to bind to Ras 4. Activated Ras binds Raf-1 5. Raf-1 phosphorylates MEK on two Ser residues activating it. 6. MEK phosphor. MAPK on a thr and tyr residue activating it. 7. MAPK moves to nuc. and phos. nuclear trans. factors like Elk1 8. Phosphor. Elk1 joins SRF to stimulate the trans. and traslation of a set of genes needed for cell division
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Sequence of events that occur when human growth hormone binds to its receptor |
1. dimerization brings together blobular proteins of the receptor on the cystolic side of the membrane (JAK2)
2. cross phos.->conform changes that activate the two kinases 3. tyrosine kinase phos. other substrates, JAK2 phosphorylates a tyrosine residue near STAT5 fomring a stable dimer 4. Dimerized STAT has a high affinity for specific binding sites on the DNA which regulate gene expression
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Adenylate Cyclase Signaling system |
Adenylate cyclase starts producing cAMP. A single hormone bound to its receptor can activat 100s of molecules. Phosphodiesterase hydrolyzes the phosphodiester bond to convert cAMP to AMP. Cafein increases the concentration of cAMP by inhibiting phosphodiesterase.
Beta-receptor- works- releases alpha subunit with GTP Alpha recptor- inhibits. releases alpha sub - with GDP.
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Tyrosine Kinase System |
JAK2 domains- cross phosphorylate eachother which causes conformational changes that activate the two kinases for other protein substrates. Then tyrosine kinase can phosphorylate other substrates such as STAT5
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purpose of the Ras system |
Stimulates cell growth and differentiation and is activated by the epidermal growth factor (EFG) and its receptor.
Purpose of Ras has an intrinsic GTPase activity which functions like a timer, terminating the signal and returning the RAS to its inactive state... can also induce the trans. of specific genes 1. EFG binds to EFG receptor, Intracellular domain phosphorylates, Grb2 binds, Sos binds, GDP binds, to Ras, which then is released and has GTP attatched!
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Purpose of Insulin Receptor |
To take undigested food out of the bloodstream.
1. insulin binds. 2. tyrosine kinase phosphorylation , phosphorylates tyrosine, and then intracellular insulin effect.s
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Oncongenes |
An oncogene is a gene that is mutated or expressed at high levels, and thus helps turn a normal cell into a tumor cell.
genes that have the potential to cause a normal cell to become cancerous cell growth & differentiation are tightly controlled processes, in tumor cells are uncontrollable rapidly proliferating cells which can grow in invasive manner and treaten life Rous Sarcoma virus caries oncogenes that induce tmors in mice
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