BSCI330: FINAL EXAM (non-cumulative portion)Signal Transduction: Water-soluble messengers- Cell surface receptors (3 types)o 1. Ligand-gated ion channels (“ionotropic receptors”) Involved in rapid synaptic signaling between nerve cells and other electrically excitable target cells, such as nerve and muscle cellso 2. G-protein coupled receptors Act by indirectly regulating the activity of a separate plasma membrane bound target protein, which is generally either an enzyme or an ion channel G-protein (often called a GTP-binding protein or receptor-activated GTP-ase)mediates the interaction between the activated receptor and the target proteino 3. Enzyme coupled receptors Function directly with enzymes that they activate- Propagation of the signal within the cello A combination of activated enzymes and small intracellular “second messenger” molecules then amplify the signal and spread it through the cell Ultimately the signal pathway activates, or inactivates, the effector proteins that alter the cell’s behavior- Intracellular “Molecular Switches” o Intracellular signaling proteins function as molecular switches 1 Switches can be activated by phosphorylation - Protein kinase adds a phosphate from ATP to the signaling protein and a phosphatase removes the phosphate Switches can be activated GTP-binding- GTP binding protein exchanges its GDP for GTP to activate the protein, which then hydrolyzes its GTP to GDP-- This is regulated by specific enzymes, GAP’s and GEF’so GAP’s (GTPase activating proteins) inactivate the protein by stimulating it to hydrolyze its bound GTP to GDPo GEF’s (guanine nucleotide exchange factors) activate the inactive protein by stimulating it to release its GDP Concentration of GTP is greater than that of GDP in the cytosol, once the GDP is ejected, the protein rapidly binds GTP- Enzymes activated by a receptor protein form protein complexes with each other and with the receptor proteino Complexes can be: Organized around a “scaffold protein”- Or assembled following receptor activation- Binding of an extracellular signal molecule to the receptor activates the receptor- Receptor phosphorylates itself at multiple sites, which then act as docking sites for intracellular signaling proteins2- Or assembled in lipid rafts on phosphorylated phosphoinositide lipids- Activated receptor leads to the increased phosphorylation of specific phospholipids in the adjacent plasma membrane- These phospholipid molecules (phosphoinositides) serve as docking sites for intracellular signaling proteins-o Some cell responses increase as the concentration of an extracellular signal moleculeincreases (blue line)o Sometimes, the cell response is driven into an abruptly different state as the signal strength increases beyond a critical value (red line) Abrupt responses can be achieved if the signal molecule is an allosteric activator that binds to several sites on the enzyme to activate it - Positive feedback control of a target protein’s activation can also cause an abrupt and prolonged activation of that protein. Negative feedback control can create oscillations-- Desensitization and termination of the response of cell-surface signalingo Desensitization- a prolonged exposure to a stimulus decreases the cells’ response to changes in the concentration of an extracellular signal molecule 3oG-protein linked receptor cascades- Signaling mechanisms that use G-protein-linked receptor proteins:o 1. Response of liver cells to adrenalin Epinephrine (adrenaline)- hormone and neurotransmitter that is released into the bloodstream from the adrenal gland as a preparation for physical activity (“fear, fight, or flight reflex”- Mobilizes glucose from stored glycogen within liver cellso The glucose enters the bloodstream in anticipation of the need for the need of muscle cells for energy- Binds to a site on the external surface of a trans-membrane protein, the “beta-adrenergic receptor protein,” found on liver cellso With epinephrine bound, this receptor protein activates a GTP-binding protein (G-protein) on the INTRACELLULAR surface of the plasma membrane G-protein activates the enzyme adenylate cyclase, which catalyzes the production of the small intracellular messenger cAMP from ATP- cAMP binds to and activates protein kinase A, which initiates 3 events:- 1. PKA enters the nucleus - See below 2. Protein kinase A phosphorylates an enzyme, glycogen synthase, which inactivates it.- Halts glycogen synthesis from glucose- less glycogen produced from glucose, allowing more glucose to be available in the bloodstream 3. PKA breaks down existing glycogen - PKA phosphorylates and activates a phosphorylase kinase -adrenergicepinephrineAdenylate cyclase4o This phosphorylase kinase phosphorylates and activates the enzyme phosphorylase- Phosphorylase stimulates the breakdown of glycogen into glucose-1-phosphate, which is then transformed into glucose by other enzymes - End result: Glucose released into bloodstream to provide energy for the response during the fear, fight, or flight reaction to adrenalin surge-o Long term effects of adrenalin on protein synthesis When PKA is activated by cAMP, it enters the nucleus- PKA phosphorylates a transcription factor protein called CREB, which binds to a particular sequence present in the promoter region of some genes.- This promotes transcription of these genes, which leads to new protein synthesis- These activated genes improve the liver cells long termability to mobilize glucose, preparing for possible further situations, which result in adrenalin release General properties of liver cells in response to epinephrine- Detection of the stimulus by a receptor proteino Beta adrenergic receptor5 Member of a large family of transmembrane receptor proteins called the 7-alpha-helical transmembrane domain receptor family Members of this family all share:- A similar core tertiary structure consisting of 7 alpha-helical transmembrane segments- A central binding site for a small ligand molecule (the “stimulus”) that is accessible from the extracellular side of the receptor protein.- A binding site for the alpha subunit of a GTP-binding protein on the intracellular surface of the receptor protein Members include:- Hormone receptor proteins- Neurotransmitter receptor proteins- Olfactory cell receptor proteins- Taste cell receptor proteins-
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