Chapter 12 Biosignaling A signal represents information that is detected by specific receptors and converted to a cellular response which always involves a chemical process the conversion of information into a chemical change Signal transduction 12 1 General Features of Signal Transduction Signal transductions are specific and sensitive o Specificity precise molecular complementarity between the signal and receptor molecules mediated by the same kinds of weak forces that mediate enzyme substrate and antigen antibody interactions o Multicellular organisms have an additional level of specificity because the receptors for a given signal or the intracellular targets of a given signal pathway are present only in certain cell types o Three factors account for sensitivity The high affinity of receptors for signal molecules Cooperativity in the ligand receptor interaction Amplification of the signal by enzyme cascades the dissociation constant Kd between signal and receptor Affinity results in large changes in receptor activation with small Cooperativity changes in ligand concentration activated and catalyzes the activation of many molecules of a second enzyme and so on when an enzyme associated with a signal receptor is Amplification o Done by enzyme cascades Desensitization occurs when a signal is present continuously o When the stimulus falls below a certain threshold the system again becomes sensitive the ability of the system to receive multiple signals and produce Integration a unified response appropriate to the needs of the cell or organism Signal transduction o A signal interacts with a receptor o The activated receptor interacts with cellular machinery producing a second signal or a change in the activity of a cellular protein o The metabolic activity of the target cell undergoes a change o The transduction event ends Six basic receptor types o G protein coupled receptors indirectly activate through GTP binding proteins or G proteins enzymes that generate intracellular second messengers Adrenergic receptor system that detects epinephrine o Receptor tyrosine kinases plasma membrane receptors that are also enzymes When activated by its extracellular ligand it catalyzes the phosphorylation of several cytosolic or plasma membrane proteins Insulin receptor Receptor for epidermal growth factor EGF R o Receptor guanylyl cyclases plasma membrane receptors with an enzymatic cytoplasmic domain The intracellular second messenger cyclic guanosine monophosphate cGMP activates a cytosolic protein kinase that phosphorylates cellular proteins and changes their activities o Gated ion channels open and close in response to the binding of chemical ligands or changes in transmembrane potential Simplest Acetylcholine receptor ion channel o Adhesion receptors interact with macromolecular components of the extracellular matrix and convey instructions to the cytoskeletal system about cell migration or adherence to the matrix Integrins o Nuclear receptors steroid receptors bind specific ligands and alter the rate at which specific genes are transcribed and translated into cellular proteins 12 2 G Protein Coupled Receptors and Second Messengers G protein coupled receptors GPCRs have three essential components o A plasma membrane receptor with seven transmembrane helical segments o An effector enzyme in the plasma membrane that generates an intracellular second messenger o And a guanosine nucleotide binding protein G protein that activates the effector enzyme Stimulated by the activated receptor Exchanges bound GDP for GTP and then dissociates from the occupied receptor and binds to a nearby enzyme altering its activity GPCRs have been implicated in o Allergies o Depression o Blindness o Diabetes o Various cardiovascular defects The Adrenergic Receptor System Acts through the Second Messenger cAMP Epinephrine causes an organism to generate energy o Flight or fight o Epinephrine binds to a protein receptor in the plasma membrane of an epinephrine sensitive cell an adrenergic receptor Four types of adrenergic receptors defined by differences in their affinities and responses to a group of agonists and antagonists o 1 o 2 o 1 o 2 Agonists Antagonists structural analogs that bind to a receptor and mimic the effects of its natural ligand effect and thereby block the effects of agonists and the natural ligand Adrenergic receptors mediate changes in fuel metabolism analogs that bind the receptor without triggering the normal o Found in muscle liver and adipose tissue o Applies to both types o Integral protein with seven hydrophobic regions o Also called serpentine receptors or hepthahelical receptors The binding of epinephrine to a site on the receptor deep within the plasma membrane promotes a conformational change in the receptor s intracellular domain that affects its interaction with the second protein stimulatory G protein or Gs on the cytoplasmic side o Active Gs stimulates the production of cAMP by adenylyl cyclase o Gs is heterotrimeric Activated by GTP Activated adrenergic receptor interacts with Gs catalyzing Inactivated by GDP replacement of bound GDP with GTP and activating Gs The and subunits of Gs then dissociate from the subunit as a dimer and Gs moves in the plane of the membrane from the receptor to a nearby molecule of adenylyl cyclase Gs is held to the membrane by a covalently attached palmitoyl Adenylyl cyclase an integral protein of the plasma membrane o Active site on the cytoplasmic face o Association with Gs stimulates the cyclase to catalyze cAMP synthesis group from ATP Gs is a GTPase that turns itself off by converting its bound GTP to GDP o Dissociates from adenylyl cyclase inactivating the cyclase Epinephrine exerts its downstream effects through the increase in cAMP that results from the activation of adenylyl cyclase o Cyclic AMP allosterically activates cAMP dependent protein kinase protein kinase A or PKA catalyzes the phosphorylation of other proteins o PKA is active when phosphorylated and begins the process of mobilizing glycogen stores in muscle and liver in anticipation of the need for energy Inactive PKA contains two identical catalytic subunits C and two identical regulatory subunits R o Inactive because an autoinhibitory domain of each R subunit occupies the substrate binding cleft of each C subunit o When cAMP binds to the R subunits they leave the C subunit and the R2C2 complex dissociates to yield two free C subunits PKA regulates several enzymes downstream in the
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