Chemistry Reference
In-Depth Information
Figure 7.2 (A) Simulated current trace of a wild-
type nAChR channel. The sampling frequency
used was 100 kHz, the Gaussian filter was
40 kHz, and the elementary current was 3 pA. The
simulation was carried out using QUB software
(www.qub.buffalo.edu). (B) Transitions of the
nAChR between microscopic states, which
illustrate the molecular events underlying the
burst shown on the expanded time scale in A. In
the standard kinetic model, receptor activation
follows the sequential binding of two ligand
molecules.
illustrated in the occupancy state diagram in Figure 7.2B. The values of the rate
constants used in the kineticmodel have been experimentally estimated for wild-type
mouse AChRs (adult-type) elicited by 1
m
M acetylcholine at
100mV applied
-
is 1700 s
1
, the opening rate constant
voltage [74]: the closing rate constant
b
is 48000 s
1
, the dissociation rate constant from diliganded to monoliganded
receptor, k
diss
, is 46 000 s
1
, and the association rate constant from monoliganded
to diliganded receptor, k
ass
,is2
a
10
8
M
1
s
1
. With these parameters, the mean time
of openings per burst, 1/
a
, is 0.59ms, the mean time of closings per burst,
1/(
b þ
k
diss
), is 11
m
is and the mean time of bursts, (1
þ b
/k
diss
)/
a þ
(
b
/k
diss
)/
(
/k
diss
), is 1.2ms.
It has been demonstrated that the two nAChRbinding sites have different af
nities
for ligands. On the other hand, the nAChR can be activated by various agonists,
whose speci
c interactions not only in
uence the binding rate constants but also the
gating kinetics [75, 76]. Current recordings of single nAChR channels activated by
ligands of different size, charge distribution, or hydrophobicity afforded a clearer
understanding of the distinct contribution of agonist-speci
c chemical groups on
docking or channel gating [76].
b
