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- Signal transduction – the conversion of information into a chemical change12.1 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 interactionso Multicellular organisms have an additional level of specificity, becausethe receptors for a given signal, or the intracellular targets of a given signal pathway, are present only in certain cell typeso 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- Affinity – the dissociation constant Kd between signal and receptor- Cooperativity – results in large changes in receptor activation with small changes in ligand concentration- Amplification – when an enzyme associated with a signal receptor is activated and catalyzes the activation of many molecules of a second enzyme,and so on.o Done by enzyme cascades- Desensitization – occurs when a signal is present continuouslyo When the stimulus falls below a certain threshold, the system again becomes sensitive- Integration – the ability of the system to receive multiple signals and producea unified response appropriate to the needs of the cell or organism- Signal transduction:o A signal interacts with a receptoro The activated receptor interacts with cellular machinery, producing a second signal or a change in the activity of a cellular proteino The metabolic activity of the target cell undergoes a changeo 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 epinephrineo 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 activitieso Gated ion channels – open and close in response to the binding of chemical ligands or changes in transmembrane potential Simplest Acetylcholine receptor ion channelo 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 Integrinso Nuclear receptors (steroid receptors) – bind specific ligands and alter the rate at which specific genes are transcribed and translated into cellular proteins12.2 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 segmentso An effector enzyme in the plasma membrane that generates an intracellular second messengero 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 Allergieso Depressiono Blindnesso Diabeteso Various cardiovascular defectsThe -Adrenergic Receptor System Acts through the Second Messenger cAMP- Epinephrine causes an organism to generate energyo Flight or fighto 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 1o 2o 1o 2- Agonists – structural analogs that bind to a receptor and mimic the effects of its natural ligand- Antagonists – analogs that bind the receptor without triggering the normal effect and thereby block the effects of agonists and the natural ligand- -Adrenergic receptors – mediate changes in fuel metabolismo Found in muscle, liver, and adipose tissueo Applies to both typeso Integral protein with seven hydrophobic regionso 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 sideo Active Gs stimulates the production of cAMP by adenylyl cyclaseo Gs is heterotrimeric Activated by GTP Inactivated by GDP Activated -adrenergic receptor interacts with Gs, catalyzing 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 fromthe receptor to a nearby molecule of adenylyl cyclase Gs is held to the membrane by a covalently attached palmitoyl group- Adenylyl cyclase – an integral protein of the plasma membraneo Active site on the cytoplasmic faceo Association with Gs stimulates the cyclase to catalyze cAMP synthesis from ATP- Gs is a GTPase that turns itself off by converting its bound GTP to GDPo Dissociates from adenylyl cyclase, inactivating the cyclase- Epinephrine exerts its downstream effects through the increase in [cAMP] that results from the activation of adenylyl cyclaseo Cyclic AMP allosterically activates cAMP-dependent protein kinase (protein kinase A or PKA) – catalyzes the phosphorylation of other proteinso 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
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