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Transduction of Extracellular Signals

Transduction of Extracellular Signals. Specific receptors in plasma membranes respond to external chemicals ( ligands ) that cannot cross the membrane: hormones , neurotransmitters , growth factors Signal is passed through membrane protein transducer to a membrane-bound effector enzyme

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Transduction of Extracellular Signals

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  1. Transduction of Extracellular Signals • Specific receptors in plasma membranes respond to external chemicals (ligands) that cannot cross the membrane: hormones,neurotransmitters,growth factors • Signal is passed through membrane proteintransducer to a membrane-bound effector enzyme • Effector enzyme generates a second messenger which diffuses to intracellular target

  2. General mechanism of signal transduction across a membrane

  3. Regulation of Hexose Transporters • Glucose enters mammalian cells by passive transport down a concentration gradient from blood to cells • GLUT is a family of six passive hexosetransporters • Glucose uptake into skeletal and heart muscle and adipocytes by GLUT 4 is stimulatedbyinsulin • Other GLUT transporters mediate glucose transport in and out of cells in the absence of insulin

  4. D. Receptor Tyrosine Kinases (TK) • Many growth factors operate by a signaling pathway involving a tyrosine kinase • TK is a multifunctional transmembrane protein containing a receptor, a transducer, and an effector • Binding of a ligand to the extracellular receptor domain activates tyrosine kinase (intracellular)

  5. Activation of receptor tyrosine kinases by ligand-induced dimerization

  6. Phosphorylated dimer phosphorylates cellular target proteins

  7. Each domain catalyzes phosphorylation of its partner

  8. Insulin receptor and tyrosine kinase activity • Insulin binds to 2 extracellular a-chains • Transmembrane b-chains then autophosphorylate • Tyrosine kinase domains then phosphorylate insulin-receptor substrates (IRSs) (which are proteins)

  9. Insulin-stimulated formation of PIP3

  10. Regulation of glucose transport by insulin

  11. Insulin Resistance and Type II Diabetes • Normal Conditions: Insulin signaling results in glucose transporter (GLUT-4) translocation from intracellular storage sites to the cell membrane (muscle, adipose tissue). • Type I Diabetes– insulin dependent, the lack of insulin due to the destruction of pancreatic ß-cells • Insulin Resistance– the inability of maximal concentrations of insulin to appropriately stimulate muscle glucose transport and other physiological responses. • Type II Diabetes– insulin independent, a global disorder of insulin signal transduction that ultimately disregulates gene expression and cell function in wide range of tissues. • Complications: neuropathy, nephropathy, retinopathy

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