Lecture 19 Synaptic transmission, vesicle fusion and cycling Why selectivity may not be important?
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Transcript of Lecture 19 Synaptic transmission, vesicle fusion and cycling Why selectivity may not be important?
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Lecture 19Synaptic transmission, vesicle fusion and cyclingWhy selectivity may not be important?Thermodynamics of channel gating by ligandStructure of Acetylcholine-binding protein (AChBP)Latest about nicotinic Ach receptor
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Erest
DepolarizationEPSP
HyperpolarizationIPSP
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mutation in Dynamin
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The Docking Complex
vesicle
plasma membrane
SNARE proteins form coiled-coils
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?
K+Cl-
K+
Cl-
I
V
EK < 0
)( KKK EEgI
driving
force
K+Cl-
K+Cl-
I
V
EK = 0
E (mV)
E – actual membrane potential
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ENa = +60 mV
EK = -90 mV
Erest = -70 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
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ACh ACh
nACh R (Na+, K+ channel)
R AR A2R A2R*closed opengate
from Unwin
A2D
desensitized
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L0, LA – equilibrium constants
KA, JA – binding constants
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C
OLO
ΔGC→O = -RT ln([O]/[C])=-RT lnL0
In the absence of ligand the O state is unfavorable, openings are rare
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C
OLO
ΔGC→O = -RT ln([O]/[C])=-RT lnL0
In the absence of ligand the O state is unfavorable, openings are rare
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ΔGC→AC = RT ln([AC]/[A][C])=RT lnKA
Initially binding of the ligand occurs with low affinity
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ΔGAC→AO = -RT ln([AO]/[AC])=-RT lnLo
Binding makes the AO state more favorable than AC, openings are frequent
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ΔGAC→OC = -RT ln([AO]/[AC])=-RT lnLA
Binding makes the AO state more favorable than AC, openings are frequent
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AOAA JRTLRTLRTKRT lnlnlnln
AOAA JLLK A
A
O
AKJ
LL
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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AChBP is released upon ACh release and then sequesters ACh
In Molluscs:
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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