Final Study Guide Specific 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 reflex o 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 ATP o 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 subunits o 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 SYNTHESIS Signal transduction how general properties apply to response of liver cells to epinephrine Detection of the stimulus by a receptor protein o Beta adrenergic receptor Transfer of a signal from a receptor protein to a cascade of signaling proteins and enzymes o 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 effects o Activation of PKA and phosphorylation of target proteins Phosphorylase kinase phosphorylase o Activation of gene transcription Detailed mechanisms and generalization o So the response of liver cells to epinephrine exemplifies many of the general properties of signal transduction o The detailed molecular mechanisms involved in responding to epinephrine can also be generalized to the response to many other external water soluble stimuli Detailed 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 segments o 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 intracellular surface of the receptor protein o 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 proteins o Neurotransmitter proteins the metabotropic neurotransmitter receptor proteins that are not in themselves ion channels o Olfactory cell and taste cell receptor proteins o Distantly rhodopsin the receptor for light in the photoreceptor cells of eyes General actions of cAMP in other cells cAMP can also bind to and directly activate ion channels that have an intracellular binding site for cAMP o cAMP gated channels can alter membrane potential especially important in the response of neurons to external stimuli that activate cAMP production o Overall cAMP can Initiate enzyme activation Initiate protein synthesis and Initiate changes in membrane potential in cells Kinase 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 activation o Amplification by the previous kinase in the cascade can interact with and activate many G proteins o Amplification at each step new active kinase molecule production is catalyzed also occurs at the receptor G protein level One receptor molecule G 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 stimuli o The modified cell at the ends of these olfactory neurons help collect stimuli o 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 about 0pA to 450 pA body of the cell o When an odor is detected the membrane potential decreases dramatically from o Olfactory function odor detection occurs at the cilia not so much the soma o The cilia are the sensory organelles that contain the transduction
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