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Final Study GuideSpecific signaling mechanisms that use cell surface receptors to respond to water-soluble signals- Response of liver cells to epinephrine (adrenaline)o Epinephrine (aka adrenaline) is a hormone and a neurotransmitter. It is released into the bloodstream from the adrenal gland as a preparation for physical activity—the “fear, fight or flight” reflexo Epinephrine mobilizes glucoses from stored glycogen in liver cells. The glucose enters the bloodstream in anticipation of the need for energy in muscle cells.o Epinephrine binds to a site on the external surface of the beta-adrenergic receptor protein found on liver cells- a trans-membrane protein. o Levels of the transduction cascade responding to epinephrine The adrenergic receptor protein (with epinephrine bound) activates a GTP-binding protein (G-protein) on the Intracellular surface of the plasma membrane of the liver cell.  The G-protein activates the enzyme Adenylate Cyclase Adenylate Cyclase catalyses the production of the small intracellular messenger cAMP from ATPo cAMP binds to and activates a protein kinase: PKA Protein Kinase A (PKA) has four subunits- 2 catalytic and 2 regulatory In its inactive state, the regulatory subunits inhibit the catalytic subunitso cAMP binds to the regulatory subunits and activates the catalytic subunits which can then phosphorylate other proteins The multi-subunit nature of PKA allows it to act as a “molecular switch” which will only turn on when 2 cAMP molecules are bound simultaneously.  This greatly reduces the chance that PKA will be activated in error by small spontaneous background fluctuations in cAMP concentration.o Activated PKA  Phosphorylates and therefore inactivates the enzyme Glycogen Synthase- thus halting glycogen synthesis from glucose Phosphorylates and therefore activates the enzyme phosphorylase kinase- which phosphorylates and activates the enzyme phosphorylase- phosphorylase stimulates breakdown of glycogen into glocuse-1-phosphate (Which then gets transformed into glucose by other enzymes) End Result: Net glycogen breakdown and release of glucose into the bloodstream to provide energy during fight or flight adrenalin surge- While glucose release is not the major short term effect of adrenaline on liver cells, there are also long term effects on protein synthesis.o Genes are activated which improve the liver cells long term ability to mobilize glucose—in preparation for late situations that result in adrenaline release.o This is achieved by a second pathway activated by PKA PKA also phosphorylates a transcription factor protein called CREB- cAMP Response Element Binding protein-, which binds to a particular sequence in the promoter region of some genes. Binding of CREB promotes transcription of these genes- NEW PROTEIN SYNTHESISSignal transduction- how general properties apply to response of liver cells to epinephrine- Detection of the stimulus by a receptor proteino Beta-adrenergic receptor- Transfer of a signal from a receptor protein to a cascade of signaling proteins and enzymeso G-Protein activates Adenylate cyclase- Amplification and relay of signal o Production of many cAMP molecules by adenylate cyclase- Activation of specific effector enzymes : Short term and Long term effectso Activation of PKA and phosphorylation of target proteins- Phosphorylase kinase, phosphorylaseo Activation of gene transcription- Detailed mechanisms and generalizationo So the response of liver cells to epinephrine exemplifies many of the general properties of signal transductiono The detailed molecular mechanisms involved in responding to epinephrine can also be generalized to the response to many other external water-soluble stimuliDetailed mechanisms- receptor and G-protein activation- The beta-adrenergic receptor protein is a member of a very large family of transmembrane receptor proteins: 7-alpha-helical transmembrane segments- Members of this receptor protein family all share:o Similar core tertiary structure with 7-alpha-helical transmembrane segmentso Central binding site for a small ligand molecules accessible from the extracellular side of the receptor protein.o A binding site for the alpha subunit of a GTP-binding protein on the intracellularsurface of the receptor proteino The many members of this protein family results in a “smorgasbord” of proteins that can interact as to form thousands of possible signaling cascades in cells- Some members of the 7-AHTS receptor family protein include:o Hormone receptor proteinso Neurotransmitter proteins- the “metabotropic” neurotransmitter receptor proteins that are not, in themselves, ion channelso Olfactory cell and taste cell receptor proteinso Distantly, rhodopsin, the receptor for light in the photoreceptor cells of eyesGeneral actions of cAMP in other cells- cAMP can also bind to and directly activate ion channels that have an intracellular binding site for cAMPo cAMP-gated channels can alter membrane potential- especially important in the response of neurons to external stimuli that activate cAMP productiono Overall, cAMP can  Initiate enzyme activation,  Initiate protein synthesis, and Initiate changes in membrane potential in cellsKinase Cascades- In liver cells, protein kinase A (PKA) starts a short “Kinase cascade”o It phosphorylates and activates phosphorylase kinase which then:o Phosphorylates and activates phosphorylase- the final effector enzyme catalyzing glycogen breakdown (Phosphorylase—glycogen breakdown)- Kinase cascades are very common in other signaling cascades as well- leading to enzyme or transcription factor activationo Amplification –at each step new active kinase molecule production is catalyzed by the previous kinase in the cascadeo Amplification also occurs at the receptor—G-protein level. One receptor moleculecan interact with and activate many G-proteinsG-protein linked- signaling mechanism- the human olfactory system- In the human olfactory system, olfactory receptor neurons attached to the olfactory nerve connect to the olfactory epithelium to pick up stimulio The modified cell at the ends of these olfactory neurons help collect stimulio The axon begins beyond the basal lamina- Function of olfactory epithelial cells is measure by membrane current due to Na+ ions flowing into the cell. o When an odor is detected, the membrane potential decreases dramatically (from about 0pA to -450 pA)o Olfactory


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UMD BSCI 330 - Final Study Guide

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