Download - Transduction of Extracellular Signals
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Transduction of Extracellular SignalsTransduction 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
• Effector enzyme generates a second messenger which diffuses to intracellular target
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General mechanism of signal transduction General mechanism of signal transduction across a membraneacross a membrane
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Regulation of Hexose TransportersRegulation 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 hexose transporters
• Glucose uptake into skeletal and heart muscle and adipocytes by GLUT 4 is stimulated by insulin
• Other GLUT transporters mediate glucose transport in and out of cells in the absence of insulin
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D. Receptor Tyrosine Kinases D. Receptor Tyrosine Kinases (TK)(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)
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• Activation of receptor tyrosine kinases by ligand-induced dimerization
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• Phosphorylated dimer phosphorylates cellular target proteins
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• Each domain catalyzes phosphorylation of its partner
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Insulin receptor and tyrosine kinase activityInsulin receptor and tyrosine kinase activity
• Insulin binds to 2 extracellular -chains
• Transmembrane -chains then autophosphorylate
• Tyrosine kinase domains then phosphorylate insulin-receptor substrates (IRSs) (which are proteins)
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Insulin-stimulated formation of PIPInsulin-stimulated formation of PIP33
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Regulation of glucose Regulation of glucose transport by insulintransport by insulin
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Insulin Resistance and Type II Diabetes
Normal Conditions: Insulin signaling results in glucose transporter(GLUT-4) translocation from intracellular storage sites to the cellmembrane (muscle, adipose tissue).
Type I Diabetes – insulin dependent, the lack of insulin due to thedestruction 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