Lectures 17-19 BCM 475 - M001
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Popular in Biochemistry
BCM 475 - M001
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Lectures 1012 Bioenergetics p 427438 Principles of Metabolism 1 Fuels are degraded and large molecules are constructed step by step in a series of linked reactions called metabolic pathwaysquot 2 An energy currency common to all life forms adenosine triphosphate ATP links energyreleasing pathways with energyrequiring pathwaysquot The oxidation of carbon fuels and powers the formation of ATPquot 4 Although there are many metabolic pathways a limited number of types of reactions and particular intermediates are common to many pathwaysquot 5 Metabolic pathways are highly regulatedquot 9 Purpose of Free Energy in Organisms 1 Mechanical work Eg Muscle contraction cell movement 2 Active transport 3 Molecular synthesis Free Energy is Obtained From the Environment Phototrophs obtain energy from the sun Chemotrophs obtain energy from the oxidation of food Metabolism Chemical reactions involved in the conversion or usage of energy Metabolic pathways are interdependent communication is crucial Degradative pathways are almost always distinctquot Metabolic Pathways Catabolic reactions Catabolism Convert energy Fuel energy cellular energy Anabolic reactions Anabolism Use energy Useful energy simple precursors complex molecules Eg synthesis of glucose fats or DNA Amphibolic pathway Pathway that can be either anabolic or catabolic The construction of metabolic pathways requires 1 Specific individual reactions that will yield only one particular product or set of productsquot and 2 Thermodynamically favorable reactions Thermodynamics of Metabolism A thermodynamically favorable reaction can drive a thermodynamically unfavorable reaction A shared chemical intermediate can couple a thermodynamically unfavorable reaction with a thermodynamically favorable one to drive the overall reaction Activated proteins with stored free energy can be used to drive thermodynamically unfavorable reactions Ionic gradients across cell membranes can be coupled to produce energetically unfavorable transport reactionsquot AG AG RT ln CD A B AG change in free energy AG standard freeenergy change standard condition implies the reactants A B C and D being present at a concentration of 10 M R gas constant T absolute temperature in Kelvins A B C D molar concentrations of the reactants AG AHsystemTASsystem G Gibbs free energy H Enthalpy T Temperature in kelvins K S Entropy Aern lt 0 9 Reaction is spontaneous exergonic reaction energy released Aern 0 9 System is in a state of equilibrium AH TAS Aern gt 0 9 Reaction is nonspontaneous endergonic reaction energy absorbed quotThe overall freeenergy change for a chemically coupled series of reactions is equal to the sum of the freeenergy changes of the individual steps Relationship Between AG and Kg1 AG 39 136 K39eq 10 AG expressed in kcal per mole Assume AG 39 was determined at a pH of 7 for all biochemical reactions Enzymes Do Not Alter Reaction Equilibrium Consider the reaction A B k1 10394 S391 kR 10396 S391 KBA kFkR 1039410396100 Enzymes increase both rate constants by the same factor ATP Is the Universal Source of Free Energy in Biological Systems Free energy is used by organisms for mechanical work active transport and molecular synthesis ATP cellular energy carrier phosphorylgroup donor Active form of ATP ATP Mg2 or Mn quotATP is an energyrich molecule because its triphosphate unit contains two phosphoanhydride bonds ATP H20 r ADP Pi Liberated free energy AG 305 kImol 73 kcalmol ATP H20 AMP PP Liberated free energy AG 456 kImol 109 kcalmol 9AG depends on the ionic strength of medium and Mg2 or Mn2 9Liberated free energy is used to drive reactions eg muscle contraction The formation of ATP from ADP and Pi on the other hand is an endergonic process that requires an input of energy light or oxidizable substrates are used as an energy source for the synthesis of ATP ThisATP ADP cycle is the fundamen tal mode of energy exchange in biological systemsquot ATP Hydrolysis Drives Metabolism by Shifting the Equilibrium of Coupled Reactionsquot Consider the reaction A B AG 4 kcalmol K eq BeqAeq 10AG 13936 X 103 The net conversion of A9 B cannot take place when the molar ratio of B to A is equal to or greater than 115 x 10393quot But by coupling the original reaction to the hydrolysis of ATP AG 73 kcalmol the new overall reaction becomes A ATP water B ADP Pi AG 33 kcalmol 4 kcalmol 73 kcalmol 33 kcalmol At pH 7 Km BleqAleq X ADpleq Pileq ATpleq 10339313936 267 X 102 At equilibrium B A is given by the following equation BleqAleq K39eq ATpleq ADpleq Pileql Coupling of ATP hydrolysis has changed K eq BeqAeq by a factor of 105 The hydrolysis of n ATP molecules changes the equilibrium ratio of a coupled reaction by a factor of 1 08quotquot In most cells ATP ADP Pi 500 M391 Therefore BeqAeq 267 x 102x 500 134 x 105 A and B can be broadly defined A 9 activated conformation of protein B 9 unactivated conformation of protein Eg myosin A 9 concentration of molecule outside of cell B 9 concentration of molecule inside cell Eg sodiumpotassium pump Structural Basis of High Phosphoryl Transfer Potential of ATP ATP H20 ADP Pi AG 73 kcalmol Glycerol 3phosphate H20 glycerol Pi AG 22 kcalmol The AG for ATP is much more negative because ATP has a stronger tendency to transfer its terminal phosphoryl group to water than does glycerol 3phosphatequot ATP has a higher phosphorylgrouptransfer potential Factors that make ATP an efficient phosphorylgroup donor 1 Resonance stabilization ADP and particularly Pi have greater resonance stabilization than does ATPquot 2 Electrostatic repulsion The hydrolysis of ATP results in a reduction of repulsion between the four negative charges in ATP 3 Stabilization due to hydration More water can bind more effectively to ADP and Pi than can bind to the phosphoanhydride part of ATP stabilizing the ADP and Pi by hydrationquot The phosphoanydride bonds of ATP are high in energy and therefore release a significant amount of free energy upon hydrolysis PhosphorylTransfer Potential Compounds with a higher phosphoryltransfer potential than ATP phosphoenolpyruvate creatine phosphate 13BPG These compounds can be used in the phosphorylation of ADP for the synthesis of ATP Creatine Kinase Eg Creatine phosphate ADP ATP creatine The phosphoryltransfer potential of ATP is intermediate to the compounds mentioned above and this intermediate position enables ATP to function efficiently as a carrier of phosphoryl groupsquot ATP is analogous to currency an intermediate that does not uctuate and thus easy to store Creatine Phosphate High energy phosphoryl reservoir Creatine Kinase Creatine phosphate ADP ATP creatine AG for creatine phosphate hydrolysis 103 kcalmol AG for ATP hydrolysis 73 kcalmol AG for the formation of ATP from creatine phosphate 30 kcalmol Keq ATP creatine ADP creatine phosphate 103136 162 Sources of ATP During Exercise Figure 157 At the start of exercise a significant amount of ATP is consumed ATP is immediately regenerated by creatine phosphate in the initial seconds of exercise The energy released upon the hydrolysis of creatine phosphate is used for the synthesis of ATP ATP synthesis9 endergonic reaction Upon depletion of creatine phosphate ATP is generated via aerobic and anaerobic metabolism The Oxidation of Carbon Fuels ATP quotImmediate donor of free energyquot Consumed within a minute of formation The turnover of ATP is very high Resting human9 40 kg of ATP consumed in one day Exercising human9 up to 05 kg ATPmin required ATPADP cycle Motion active transport signal amplification and biosynthesis can take place only if ATP is continually regenerated from ADPquot The carbon in fuel molecules such as glucose and fats is oxidized to carbon dioxide The resulting electrons are captured and used to regenerate ATP from ADP and Piquot The AG of oxidation for methane with carbon in its most reduced form is 196 kcalmol The AG of oxidation for carbon dioxide with carbon in its most oxidized form is O kcalmol More reduced9 more free energy released The more reduced state of carbon in fats compared to those of glucose makes fats a better fuel source for ATP generation The energy of oxidation is initially trapped as a highphosphoryItransferpotentiaI compound and then used to form ATPquot Lecture 1014 Signal Transduction I p 401411 SignalTransduction Pathways ENNtquot Figure 141 Involves the binding of a signal molecule to a specific receptor Epinephrine betaadrenergic receptor 9 energystore mobilization Insulin insulin receptor 9 increased glucose uptake Epidermal growth factor EGF EGF receptor 9 expression of growthpromoting genes Principles of Signal Transduction Signal Stimulus 9 Release of primary messenger or signal molecule Reception Primary messenger acts as a ligand and binds to extracellular region of transmembrane protein Receptor transfers information received from the signal molecule into the intracellular region of cell Delivery of the Message Inside the Cell by the Second Messengerquot Second messengers are intracellular molecules that change in concentration in response to environmental signals and mediate the next step in the molecular information circuitquot Eg of second messengers cAMP cGMP calcium ion 1P3 DAG Second messengers amplify the intracellular signal Second messengers are often free to diffuse to other cellular compartments where they can in uence processes throughout the cellquot The usage of a common second messenger in different signaling pathways can result in cross talk or input from several signaling pathwaysquot Cross talk could benefit the cell by enabling more efficient regulation of cell activity but it could also harm the cell by resulting in misinterpretation of changes in secondmessenger concentrationquot Second messengers activate many protein kinases Activation of Effectors Activation of pumps channels enzymes and transcription factors Signaling Process Terminated Once the effectors involved in metabolic pathways are activated the signal must be terminated to enable the cell to appropriately respond to new signals Epinephrine Hormone Secreted by adrenal glands Secreted in response to internal and external stressors Epinephrine Signaling Pathway 1 Binding of epinephrine to the betaadrenergic receptor BAR Betaadrenergic receptor BAR Seventransmembranehelix 7TM receptor Receptor composed of seven helices spanning membrane Biological functions of 7TM receptors include hormone action hormone secretion neurotransmission chemotaxis etc Rhodopsin First 7TM receptor structure determined Present in retina of eye Detects photons Responsible for visual sensation Upon exposure to light rhodopsin experiences a structural change that is responsible for initiating the receptors biological function Structurally similar to threedimensional structure of Bzadrenergic receptor 2 Activation of BAR receptor Upon binding of epinephrine to the 7TM receptor BAR undergoes a conformational change 3 Activation of G protein The conformational change of BAR leads to the activation of the G protein located in the intracellular region of the cell G protein binds guanyl nucleotides G protein in unactivated state G protein is bound to GDP Heterotrimeric G protein a 8 and y subunits a subunit binds nucleotide GDP a and y subunits are bound to the membrane via attached fatty acids G protein in activated state GTP replaces GDP on a subunit upon the binding of epinephrine to BAR a subunit undergoes a conformational change upon guanine nucleotide exchange GDP 9 GTP a subunit dissociates from By dimer By dimer forms a stable complex with no enzymatic activity This dissociation of the a subunit transmits the signal that the receptor BAR has bound its ligand epinephrinequot The alpha subunit of the G protein no longer has high a high affinity for G y but rather has a high binding affinity for adenylate cylase 4 Activation of adenylate cyclase Adenylate cyclase is activated by the activated G protein After GTP newly formed a subunit dissociates from the By dimer it binds to adenylate cyclase the interaction of this new alpha subunit with adenylate cyclase favors a more catalytically active conformation of the enzyme thus stimulating cAMP productionquot Adenylate cyclase Enzyme Converts ATP 9 cAMP Membrane protein with 12 membranespanning helices and two large intracellular domains that contain the catalytic apparatusquot 5 Increased cAMP 6 Activation of protein kinase A PKA and other effectors cAMP activates PKA Functions of activated PKA 1 Glycogen metabolism PKA phosphorylates two enzymes that lead to the breakdown of glycogen and the inhibition of further glycogen synthesisquot 2 Gene expression PKA alters gene expression by phosphorylating the CAMP response element binding CREE protein 3 Learning and memory PKA phosphorylation of key proteins in the synapse alter neuronal excitability and ultimately cause learning and memory at the single cell levelquot G Proteins Continuously Cycle Through Active and Inactive States The alpha subunit of the G protein has intrinsic GTPase activity This intrinsic property is responsible for the hydrolysis of bound GTP 9 GDP and Pi On hydrolysis of the bound GTP by the intrinsic GTPase activity of the alpha subunit the alpha subunit reassociates with the beta gamma dimer to form the originial heterotrimeric G protein thereby terminating the activation of adenlyate cyclasequot Signal Termination 1 Signal molecule eg epinephrine dissociates from receptor BAR 2 The phosphorylation of a specific residue in the Cterminus of the receptor leads to the deactivation of the receptor in addition quotBarrestin binds to the phosphorylated receptor and further diminishes its ability to activate G proteins Phosphoinositide Cascade Also involves a 7TM receptor Eg of phosphoinositide cascade with angiotensin II receptor G protein activated in this cascade is called Gaq Gaq in GTP form binds to and activates the beta isoform of the enzyme phospholipase Cquot Second messengers diacylglycerol DAG and 145trisphosphate 1P3 are cleaved from phosphatidylinositol 45bisphosphate PIPz by phospholipase C 1P3 Shortlived messenger few seconds Dephosphorylation to inositol occurs by action of a series of phosphatases or a kinase can produce 1P2 which is then degraded to inositol by other enzymesquot Lithium is an effective inhibitor of the phosphatases resulting in stabilization of the 1P3 pool used to treat bipolar affective disorderquot 1P3 binds to specific IP3gated calcium channel proteins on intracellular membranes of endoplasmic or sarcoplasmic reticulum The binding of 1P3 to those channels results in the in ux of calcium ion into the cytoplasm from the ER 1P3 increases Ca2 Calcium ions subsequently act as a signaling molecule DAG Stays in plasma membrane Activates protein kinase C PKC DAG can only activate PKC by binding to it when PKC has bound calcium ions Calcium ions facilitate the DAGmediated activation of protein kinase Cquot Calcium Ions Properties that make calcium ions a common intracellular messenger 1 Fluctuations in the concentration of calcium ions is easy to detect Extracellular calcium ion concentration 9 SmM Cytoplasmic calcium ion concentration 9 100 nM The significantly lower intracellular concentration of calcium ions enables the easy detection of increased calcium ion concentrations within the cell 2 Calcium ion can bind tightly to proteins and induce substantial structural rearrangementsquot The capacity of Ca2 to be coordinated to multiple ligands from six to eight oxygen atoms enables it to crosslink di ferent segments of a protein and induce significant conformational changesquot Calcium Imaging Dyes such as Fura2 are used to detect intracellular changes in calcium ion concentration Because calcium ions bind well to negatively charged and uncharged oxygen atoms fura2 binds calcium ions through appropriately positioned oxygen atoms within its structurequot Fura2 bound to calcium ions will uoresce and enable detection of calcium ion concentration and concentration gradients Calmodulin 17kd protein Possesses four calcium ion binding sites At cytoplasmic concentrations above about 500 nM Ca2 binds to and activates calmodulinquot EFhand protein Formed by a helixloophelix unit an EF hand is a binding site for Ca2 in many calciumsensing proteinsquot When calcium ions bind to calmodulin the protein experiences a structural change in its EF hands exposing hydrophobic surfaces that can be used to bind other proteinsquot Calcium ions act as second messengers and calmodulin acts as a secondmessenger binding protein Upon binding of calcium to calmodulin enzymes pumps and other proteins are stimulated Calcium ioncalmodulin complexes stimulate calmodulindependent protein kinases that phosphorylate many different proteins and regulate fuel metabolism ionic permeability neurotransmitter synthesis and neurotransmitter releasequot Lecture 1016 Signal Transduction II p 411422 Insulin Signaling Increased blood glucose 9 insulin insulin receptor 9 increased glucose uptake Insulin Peptide hormone Two chains linked by three disulfide bonds Insulin receptor Aka receptor tyrosine kinase Dimer Two identical units one disulfide bond One unit a chain 8 chain a subunit extracellular 8 subunit intracellular The two 1 subunits move together to form a binding site for a single insulin moleculequot The closing up of an oligomeric receptor or the oligomerization of monomeric receptors around a bound ligand is a strategy used by many receptors to initiate a signal particularly by those containing a protein kinasequot The 8 subunit contains a protein kinase domain Protein kinase domain of insulin receptor The 8 subunit contains a protein kinase domain Tyrosine kinase Unlike PKA this insulinreceptor kinase catalyzes the transfer of a phosphoryl group from ATP to the hydroxyl group of tyrosine rather than serine or threoninequot Inactive without covalent modification of protein kinase domain Insulin Signaling Pathway 1 One insulin molecule binds to the insulinreceptor dimer 2 Activation of Insulin Receptor Without covalent modification of the protein kinase domain the insulin receptor is inactive An activation loop is present at the center of the protein kinase domain of the insulin receptor When the two alpha subunits of the insulin receptor come together to form an insulinbinding site the intracellular beta subunits with the protein kinase domains also come closer to each other With the two beta subunits forced together the kinase domains catalyze the addition of phosphoryl groups from ATP to tyrosine residues in the activation loopsquot Inactive insulin receptor kinase unphosphorylated activation loops Active insulin receptor kinase phosphorylated tyrosine residues in activation loop When the tyrosine residues in the activation loop are phosphorylated the protein kinase domain experiences a structural change The kinase structure adopts a more compact conformation and this conformation is catalytically activequot 3 Phosphorylated IRS proteins In addition to the tyrosine residues in the activation loop other sites within the receptors are also phosphorylated crossphosphorylation The other phosphorylated sites on the beta subunit of the insulin receptor are then bound by other substrates including insulinreceptor substrates IRS Eg IRS1 and IRS2 Homologous proteins Nterminus pleckstrin homology domain binds phosphoinositide phosphotyrosinebinding domain The two domains mentioned above anchor the IRS protein to the insulin receptor and the associated membranequot Both have four TyrXXMet sequences These sequences are also substrates for the activated insulinreceptor kinasequot With the phosphorylation of the tyrosine residues of the abovementioned sequences of the IRS proteins to form phosphotyrosine residues IRS molecules can act as adaptor proteinsquot 4 Localized phosphoinositide 3kinase The phosphotyrosine residues of the IRS proteins are recognized by Src homology 2 SHZ domains The negatively charged phosphotyrosine residue interacts with two arginine residues that are conserved in essentially all SH2 domainsquot Phosphoinositide 3kinases PI3Ks Contain SH2 domains specific to phosphotyrosine residues Bind to phosphorylated sites on IRS Add a phosphoryl group to the 3position of inositol in phosphatidylinositol 45 bisphosphate PIP2quot 5 Phosphotidylinositol345trisphosphate PIP3 Formation Phosphoinositide 3kinases bind through their SH2 domains to IRS proteins and are drawn to the membrane where they can phosphorylate Ple to form phosphotidylinositol345trisphosphate PIP3quot 6 Activated PIP3dependent protein kinase PIP3 activates PDKl PIP3dependent protein kinase 7 Activated Akt protein kinase The activated PDKl phosphorylates and activates Akt another protein kinasequot 8 Increased glucose transporter on cell surface Akt moves through the cell to phosphorylate targets that include components that control the trafficking of the glucose receptor GLUT4 to the cell surface as well as enzymes that stimulate glycogen synthesisquot Termination of Insulin Signaling Protein tyrosine phosphatases 9 remove phosphoryl groups from tyrosine residues on the insulin receptor and the IRS adaptor proteinsquot Lipid phosphatases 9 hydrolyze PIP3 to PIPZquot Protein serine phosphatases 9 remove phosphoryl groups from activated protein kinases such as Aktquot Epidermal growth factor EGF 6 kg polypeptide Has 3 intrachain disulfide bonds Stimulates the growth of epidermal and epithelial cellsquot EGF receptor EGFR Dimer Two identical subunits Each subunit contains an intracellular protein tyrosine kinase domain that participates in crossphosphorylation reactionsquot The EGFR consists of monomers of each subunit until the binding of EGF dimerizes the EGFR Each EGFR binds a single molecule of EGF in its extracellular domainquot Therefore the dimerization of the EGFR enables the binding of two EGF molecules Each EGF molecule lies far away from the dimer interface that includes a socalled dimerization arm from each monomer that reaches out and inserts into a binding pocket on the other monomerquot In an unactivated EGFR the dimerization arm binds to a domain within the same monomer that holds the receptor in a closed configurationquot Her2 receptor Structural conformation without ligand extended the ligandbound EGFR has an extended structure Overexpressed in some cancers EGF signaling pathway 1 EGF EGFR 2 Phosphorylated receptor Upon EGF binding the EGFR undergoes dimerization and the Cterminal tail of one subunit moves closer to the active site of the other subunit Cterminal tails are rich in tyrosine The Cterminal tails of the kinase domain of EGFR are phosphorylated upon EGFR dimerization Phosphotyrosines formed on EGFR 3 Binding of Grb2 Grb2 proteins contain SH2 domains that have high affinity for phosphotyrosines Grb2 also contains two SH3 domains The SH2 domains of Grb2 bind to the phosphotyrosine residues of EFGR 4 Binding of Sos Sos protein binds to SH3 domains of Grb2 5 Activated Ras Ras binds to Sos Ras Small G protein Unactivated form contains GDP Upon binding to Sos GTP replaces GDP and activates Ras Sos functions as a guaninenucleotideexchange factor GEFD 6 Activated Raf Active Ras with GTP binds Raf Raf experiences a structural change and is subsequently activated Both Ras and Raf are anchored to the membrane through covalently bound isoprene lipidsquot 7 Activated MEK Activated Raf phosphorylates MEKs proteins kinases 8 Activaked ERK Activated MEK activates extracellular signalregulated kinases ERKs 9 ERK phosphorylates transcription factors 10 Changes occur in gene expression Small G Proteins Small GTPases Subfamilies Ras Rho Arf Rab and Ran Function growth differentiation cell motility cytokinesis transport of materials throughout the cellquot Cycle between an active GTPbound form and an inactive GDPbound formquot Monomeric Termination of EGF Signaling Protein phosphatases Remove phosphoryl groups from tyrosine residues on the EGF receptor and from serine threonine and tyrosine residues in the protein kinases that participate in the signaling cascadequot Ras is inactivated by its intrinsic GTPases activity GTPaseactivating proteins GAPs can speed up the conversion of activated Ras with GTP to inactive Ras with GDP GAPs facilitate GTP hydrolysis Recurring Themes of SignalTransduction Pathways Protein kinases are central to many signaltransduction pathwaysquot Epinephrine pathway cAMP dependent protein kinase Insulin and EGF pathways 9 receptors contain protein kinase domains Second messengers participate in many signaltransduction pathwaysquot Common second messengers 9 cAMP calcium ion 1P3 lipid DAG quotSpecialized domains that mediate specific interactions are present in many signaling proteins Eg Pleckstrin homology domains SHZ domains SH3 domains Signaltransducti0n pathways have evolved in large part by the incorporation of DNA fragmen ts encoding these domains in to genes encoding pathway componen tsquot Defects in SignalTransduction Pathway Rous sarcoma virus Retrovirus Causes cancer of tissues in chickens Carries vsrc oncogene that can lead to cancer csrc is a protooncogene that can become an oncogene when mutated vsrc encodes vSrc a protein tyrosine kinase that includes SHZ and SH3 domainsquot vSrc vs cSrc cSrc contains a key tyrosine residue near its Cterminal end that when phosphorylated is bound intramolecularly by the upstream SH2 domain m interaction maintains the kinase domain in an inactive conformationquot vSrc lacks the key tyrosine residue and is therefore always active Tumors often result from a mutation in a gene encoding Ras While Ras proteins must convert back to their inactive GDP form some mutations prevent this and trap Ras in its activated form and stimulate cell growth both with and without the presence of a signal molecule Tumorsuppressor genes Contribute to cancer development only when both copies of the gene normally present in a cell are deleted or otherwise damagedquot Eg genes encoding EGFsignaling pathway termination phosphatases Therapeutic Approaches Monoclonal antibodies For tumors with overexpressed receptor tyrosine kinases a therapeutic approach is to produce monoclonal antibodies to the extracellular domains of the offending receptorsquot Eg Cetuximab Erbitux is a monoclonal antibody that inhibits the overexpression of EGFR in colorectal cancers by competing with EGF for the binding site on the receptorquot Eg Trastuzumab Herceptin inhibits the overexpression of Her2 observed in breast cancers Protein kinase inhibitors as anticancer drugs Eg Gleevec inhibits BcrAbl kinase that is overexpressed in leukemia cells In chronic myelogenous leukemia parts of chromosomes 9 and 22 are reciprocally exchanged causing the bcr and abl genes to fusequot and become the bcrabl gene that overexpresses the BcrAbl kinase and causes cancer Cholera and Whooping Cough Are Due to Altered GProtein Activityquot Cholera Diarrheal disease Choleragen9 cholera toxin Result of active G protein trapped in its active state and subsequent continuous activation of protein kinase A PKA phosphorylates a chloride channel leading to its opening and phosphorylates a sodium ionhydrogen ion exchanger leading to the inhibition of sodium absorption Therefore PKA causes an excessive loss of NaCl and water Pertussis Whooping cough Result of a G protein trapped in its inactive state Note Quotations indicate text obtained directly from textbook References Berg Jeremy John Tymoczko and Lubert Stryer Biochemistry 7th ed WH Freeman 2012 l 246 Print
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