lecture 19 synaptic transmission, vesicle fusion and cycling why selectivity may not be important?
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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. E rest. Depolarization EPSP. Hyperpolarization IPSP. - PowerPoint PPT PresentationTRANSCRIPT
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
Erest
DepolarizationEPSP
HyperpolarizationIPSP
mutation in Dynamin
The Docking Complex
vesicle
plasma membrane
SNARE proteins form coiled-coils
from A. Brunger
Postsynaptic ionotropic receptors:Nicotinic ACh receptor (nAChR)
Glutamate receptor (GluR)AMPA, NMDA subtypes
GABAA receptor
Glycine receptor
excitatory (cation channels)
inhibitory (Cl- channels)
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
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
ACh ACh
nACh R (Na+, K+ channel)
R AR A2R A2R*closed opengate
from Unwin
A2D
desensitized
L0, LA – equilibrium constants
KA, JA – binding constants
C
OLO
ΔGC→O = -RT ln([O]/[C])=-RT lnL0
In the absence of ligand the O state is unfavorable, openings are rare
C
OLO
ΔGC→O = -RT ln([O]/[C])=-RT lnL0
In the absence of ligand the O state is unfavorable, openings are rare
ΔGC→AC = RT ln([AC]/[A][C])=RT lnKA
Initially binding of the ligand occurs with low affinity
ΔGAC→AO = -RT ln([AO]/[AC])=-RT lnLo
Binding makes the AO state more favorable than AC, openings are frequent
ΔGAC→OC = -RT ln([AO]/[AC])=-RT lnLA
Binding makes the AO state more favorable than AC, openings are frequent
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
AChBP is released upon ACh release and then sequesters ACh
In Molluscs:
from Sixma et al.
AChBP: 210 aa per subunit, pentamer
from Sixma et al.
nicotine carbamylcholine