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Wed review

Wed review. Ion channels—characteristics? K + channel How is selectivity for K + conferred? Na + channel What opens the channel? nACh receptor channel What conformational change is necessary to open the channel? Biosignaling/signal transduction What are common characteristics?

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Wed review

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  1. Wed review • Ion channels—characteristics? • K+ channel • How is selectivity for K+ conferred? • Na+ channel • What opens the channel? • nACh receptor channel • What conformational change is necessary to open the channel? • Biosignaling/signal transduction • What are common characteristics? • Gated ion channels • Neuronal signaling • Facilitated by release of neurotransmitters (like ACh)

  2. Signaling in nervous system • Neurons carry nerve impulse (action potential) from one end of cell (cell body) through elongated extension (axon) • Impulse triggers neurotransmitter (ACh) release into post-synaptic cleft • NT (ACh) carries signal to adjacent cell/neuron

  3. Biosignaling in the nervous system—gated ion channels • nACh receptor • 3 conformations • No ligand closed ‘resting’ state • ACh  open ‘excited’ • Na+ and Ca+2 flow • ACh for a long time  closed ‘desensitized’

  4. Biosignaling in the nervous system—nACh receptor • Resting state Vm = -60 mV • nACh receptors, Na+ channels, K+ channels, Ca+2 channels are closed • ACh released by excited neuron • Diffusion synaptic cleft • Interacts with ACh receptor on next neuron • Channel opens and Na+ and Ca+2 pass • Depolarizes the membrane to –40 mV

  5. Biosignaling in the nervous system—Na+, K+ channels • In response to membrane depolarization ( –40 mV) • Na+ channels open • Na+ in further depolarizes the cell locally • Vm increases to +30 mV • Na+ channels close • K+ channels open (response to large depolarization) • K+ out repolarizes the cell locally • Vm returns to negative • K+ channels close

  6. Biosignaling in the nervous system • ‘Wave’ of depolarization pulse travels down axon of neuron • opening and closing of Na+ and K+ channels • Distal tip of axon • Ca+2 channels open in response to depolarization • Ca+2 in, causing release of ACh from vesicles • ACh binds to receptors on adjacent neuron ….. • What happens when we inhibit system?

  7. Toxins/inhibitors • Na+ channel inhibition • Tetrodotoxin • Saxitoxin • AChreceptor inhibition • Tubocurarine • Cobratoxin • a-bungarotoxin • Block signals nerves  muscles • Paralysis and death

  8. Toxins • Clostridium botulinum • Botulism • Inhibition ACh release • Respiratory paralysis (in serious cases) • a-latrotoxin (black widow) • Abnormal release of ACh • Rarely fatal • Nausea, mild paralysis

  9. Receptor Enzymes • 2 functional domains • Extracellular ligand binding • Intracellular enzyme active site • 2 most common • ***Tyr-kinase enzymes • Insulin receptor • Guanylyl cyclase receptor enzymes • synthesize cGMP as a 2nd messenger • Atrial natriuretic factor receptor

  10. Insulin receptor • Tyrosine kinase enzyme • Phosphorylates Tyr • Homodimer of ab subunits • a insulin bindingdomain • extracellular • 1 insulin site between the 2 a • b enzyme activity • Spans membrane and intracellular • Both b haveTyr kinase activity when active

  11. Insulin receptor • Insulin binds to a-subunits • b-subunits undergo ‘auto’/cross phosphorylation • b1 phosphorylates b2 and b2 phosphorylates b1 • Conformational change • Kinase is ‘activated’ to phosphorylate other proteins • What does insulin do?

  12. Activated Insulin receptor • Phosphorylation of IRS-1 (insulin-receptor substrate 1) • Docking site for proteins with SH2 domains • IRS-1 binds Grb2 • Has SH3 domain- affinity for prolines • SOS complexes (via SH3) • Binds Ras GDP release and GTP binding • Activates Raf 1 (protein kinase) to phosphorylate MEK (kinase), which phosphorylates ERK (kinase) • ERK enters nucleus and phosphorylates proteins (Elk-1) modulation of insulin-related gene transcription ‘MAP (mitogen activating Pathway) kinase cascade’

  13. Activated Insulin receptor • Phosphorylated IRS-1 • Docking site for proteins with SH2 domains • Binds PI-3K • Converts PIP2 to PIP3 • PIP3 binds to protein kinase B (PKB) • Phosphorylated and activated by PDK1 • Active PKB—2 effects • 1. Stimulates movement of glucose transporters to plasma membrane • 2. Phosphorylates (and inactivates) glycogen synthase kinase 3 (GSK3) • Stimulates glycogen synthesis because glycogen synthase is ‘active’

  14. Steroid/Nuclear receptors • Steroids •  hydrophobic • In serum protein bound • Simple diffusion across membrane • Bind to receptor proteins in nucleus trigger conformational change • 2 domains • Ligand binding domain • DNA binding domain • Modifies gene expression • binds to a regulatory sequence in DNA (hormone response element)

  15. Steroid/Nuclear receptors Stryer ‘Biochemistry’ 2004

  16. Steroid/Nuclear receptors • Agonists • Molecules that bind to receptor and trigger response • Anabolic steroids • Agonists of androgen receptor • Stimulates gene expression lean muscle mass

  17. Steroid/Nuclear receptors • Antagonists • Molecules that bind to receptor but do not trigger response • Like competitive inhibitors (enzymes) • Tamoxifen—estrogen receptor antagonist • Slows growth of cancer cells that depend on estrogen for growth Stryer ‘Biochemistry’ 2004.

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