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1、Chapter 12 Biosignaling,the concept of biosignalingfeatures of biosignalingthe four major pathwaysregulation of pathways,Lectured by Dr. Qin Yongmei (秦咏梅): June 16, 2007,Why do we need biosignaling pathways ?,functional integration of distant organs, tissues and cells requires communication;Signalin
2、g is perhaps a primal requirement to respond to our environment;The foundation of any complex response pathway lies with cellular biochemicals.,Cellular response,Growth & Differentiation Growth factors DNA replication,Death apotosis,Degradation oxidation of fatty acids,Release neurotransmitters horm
3、ones,Storage glucose glycogen,Requirement of Biosignaling,requires a receptor to detect signals;the receptor must link to or generate an intracellular response;Such linking molecules are known as “second messengers”;This transduction system must meet four specific criteria.,Criterion 1: specificity,
4、High specificity only the target cell is influenced;Receptor binding site ligand (signal molecule)complementary and non-covalent interactionfollows the law of mass action,Criterion 2: amplification,often short-lived & low concentration,A single receptor binding event may elicit responses inmultiple
5、enzyme,Criterion 3: Desensitization,feedback control,the aim of biosignaling is to produce a rapid and majorcellular response to a transient signal.,Criterion 4: Integration,cells frequently receive multiple signals; there are manyreciprocal pathways within cells.,Six general types of signal transdu
6、cers,Gated ion channel,Receptor enzyme,Serpentine receptor (via G-protein),Steroid receptor,Receptor with no intrinsic enzyme activity,Adhesion receptor,Type I: gated-ion channels,a simple signal transduction system mediating neural transmission;Acetylcholine (Ach) diffuses across synaptic cleft ofn
7、euromuscular junction to acetylcholine receptortwo Ach binding sites exhibit positive co-operativityEntry of Na+, Ca2+ (propagate the initial event):depolarization that affects other channelscontraction in muscleDesensitization and channel closure: If the Ach is not rapidly metabolized by acetylchol
8、inesterase, the receptor undergoes a closed conformation with tightly bound to Ach. The slow release of Ach from its binding site eventually allows the receptor to return to its resting state.,Role of voltage-gated and ligand-gated ion channels in neural transmission,axon of presynaptic neuron,Cell
9、body of postsynaptic neuron,Three stages of acetylcholine receptor,Type 2: receptor-enzyme units,(a) tyrosine kinasesinsulin receptor: prototype forthis signaling pathway.the receptor complex: extracellular ligand binding site cytosolic catalytic domain;The enzyme is a tyrosine kinase, which phospho
10、rylate tyrosine residues in specific target proteins.,Physiological role of insulin a. High blood glucose concentration causes increased secretion of insulin and decreased secretion of glucagon;b. Stimulate the glucose transporter, thus the uptake of glucose by muscle and adipose tissue cells;Regula
11、te both fuel metabolism and gene expression: kinase cascade (protein phosphorylation) growthresponse that include increases in synthesis of DNA and mRNA promoting anabolic processes/inhibiting catabolic onespredominantly in muscle, fat and liver tissue; glycogen (in liver and muscle) triacylglycerol
12、s (in adipose tissue),Tyr kinase domain of insulin-receptor,Inactive (unphosphorylated),Active (triply phosphorylated),IRS: insulin receptor substrateprotein kinase :Raf-1, MEK, MAPK(phosphorylate Ser or Tyrresidue)MAPK (ERK, extracellularregulated kinase): mitogen- activated protein kinase;MEK (MAP
13、KK): mitogen-activated, ERK-activating kinase,Multivalent scaffold proteins and membrane rafts,Many signalling proteins are multivalent and they can interact with several different proteins simultaneously to form multiprotein signalling complexes.,Red: SH2 domain or PTB domain Orange: SH3 domain,Grb
14、2-Sos-Ras-MAPK pathway,PI-3K-PKB pathway,Blue: PH domain (plextrin homology),Some binding modules of signaling proteins,Adaptor,Scaffold,Kinase,Phosphatase,Ras signaling,Transcription,Signal regulation,Phospholipid second- messenger signaling,Protein modules, such as SH2 domain and PTB (phosphotyros
15、ine- binding domain), bind phosphorylated Tyr, Ser or Thr residues in partner proteins.,Activation of glycogen synthase by insulin,Autoinhibited,Active,Autoinhibited,Active,Src Tyr kinase,GSK3: glycogen synthase kinase 3,Dephosphorylation,Membrane rafts and caveolae may segregate signaling proteins,
16、caveolin,GPI linked enzymes,palmitolated,Src-like kinase & trans-membrane receptors,Caveolae associated signalling receptors,Diabetes is a defect in insulin production or actiona. Diabetes mellitus is caused by a deficiency in the secretion or action of insulinb.Two major clinical classes of the dis
17、ease:Type I: insulin-dependent diabetes mellitus (IDDM)Type II: non-insulin-dependent diabetes mellitus (NIDDM)c. Glucosuria: excretion of large amounts of glucose in the urined. Excessive but incomplete oxidation of FAs in the liver (ketone bodies production acidosis and ketoacidosis) e. glucose-tolerance test,
