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Lecture 19 Synaptic transmission, vesicle fusion and cycling Why selectivity may not be important?

Lecture 19 Synaptic transmission, vesicle fusion and cycling Why selectivity may not be important? Thermodynamics of channel gating by ligand Structure of Acetylcholine-binding protein (AChBP) Latest about nicotinic Ach receptor. E rest. Depolarization EPSP. Hyperpolarization IPSP.

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Lecture 19 Synaptic transmission, vesicle fusion and cycling Why selectivity may not be important?

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  1. Lecture 19 Synaptic transmission, vesicle fusion and cycling Why selectivity may not be important? Thermodynamics of channel gating by ligand Structure of Acetylcholine-binding protein (AChBP) Latest about nicotinic Ach receptor

  2. Erest Depolarization EPSP Hyperpolarization IPSP

  3. mutation in Dynamin

  4. The Docking Complex vesicle SNARE proteins form coiled-coils plasma membrane from A. Brunger

  5. Postsynaptic ionotropic receptors: Nicotinic ACh receptor (nAChR) Glutamate receptor (GluR) AMPA, NMDA subtypes GABAA receptor Glycine receptor excitatory (cation channels) inhibitory (Cl- channels)

  6. E (mV) K+ K+ K+ K+ Cl- Cl- Cl- Cl- I I V V EK = 0 EK < 0 What is driving force? driving force E – actual membrane potential

  7. ENa = +60 mV Erest = -70 mV EK = -90 mV - it is known that Na+ influx causes depolarization, and K+ efflux causes hyperpolarization. Yes. Hmmm, …but nAChR passes both of ions! Why does it lead to excitation? Ethreshold

  8. nACh R (Na+, K+ channel) A2D A2R* R AR A2R open closed gate desensitized from Unwin

  9. L0, LA – equilibrium constants KA, JA – binding constants

  10. C LO O In the absence of ligand the O state is unfavorable, openings are rare ΔGC→O = -RT ln([O]/[C])=-RT lnL0

  11. C LO O In the absence of ligand the O state is unfavorable, openings are rare ΔGC→O = -RT ln([O]/[C])=-RT lnL0

  12. Initially binding of the ligand occurs with low affinity ΔGC→AC = RT ln([AC]/[A][C])=RT lnKA

  13. Binding makes the AO state more favorable than AC, openings are frequent ΔGAC→AO = -RT ln([AO]/[AC])=-RT lnLo

  14. Binding makes the AO state more favorable than AC, openings are frequent ΔGAC→OC = -RT ln([AO]/[AC])=-RT lnLA

  15. The change in equilibrium constant between the states equals to the change in affinity to the ligand that occurs with opening. Consider what should be strong agonist, weak agonist or competitive blocker

  16. In Molluscs: AChBP is released upon ACh release and then sequesters ACh from Sixma et al.

  17. AChBP: 210 aa per subunit, pentamer from Sixma et al.

  18. nicotine carbamylcholine

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