Synaptic transmission, vesicle fusion and cycling

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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
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Depolarization EPSP
Hyperpolarization IPSP
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mutation in Dynamin
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The Docking Complex
vesicle
SNARE proteins form coiled-coils
plasma membrane
from A. Brunger
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Postsynaptic ionotropic receptors Nicotinic ACh
receptor (nAChR) Glutamate receptor (GluR) AMPA,
NMDA subtypes GABAA receptor Glycine receptor
excitatory (cation channels)
inhibitory (Cl- channels)
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What is driving force?
driving force
E actual membrane potential
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- 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
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nACh R (Na, K channel)
A2D
A2R
R
AR
A2R
open
closed
gate
desensitized
from Unwin
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L0, LA equilibrium constants KA, JA binding
constants
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In the absence of ligand the O state is
unfavorable, openings are rare
?GC?O -RT ln(O/C)-RT lnL0
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In the absence of ligand the O state is
unfavorable, openings are rare
?GC?O -RT ln(O/C)-RT lnL0
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Initially binding of the ligand occurs with low
affinity
?GC?AC RT ln(AC/AC)RT lnKA
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Binding makes the AO state more favorable than
AC, openings are frequent
?GAC?AO -RT ln(AO/AC)-RT lnLo
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Binding makes the AO state more favorable than
AC, openings are frequent
?GAC?OC -RT ln(AO/AC)-RT lnLA
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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
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In Molluscs
AChBP is released upon ACh release and then
sequesters ACh
from Sixma et al.
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AChBP 210 aa per subunit, pentamer
from Sixma et al.
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nicotine
carbamylcholine
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