1.6.2
The Nicotinic Acetylcholine Receptor
The nicotinic acetylcholine receptor (nAChR) is present in the postsynaptic membrane at neuromuscular junctions and other synapses, including in the central nervous system (for recent reviews,
see e.g. Changeux and Edelstein 2005; Changeux 2012; Corringer et al. 2012; Sine 2012; Cecchini
and Changeux 2015). Upon binding the neurotransmitter acetylcholine (ACh) released in the synaptic
cleft by the nerve terminal, it opens a TM cation-specific channel. As briefly mentioned above (§ 1.3),
the net entry of positive charges that results, mainly due to Na
+ ions, depolarizes the membrane to the
point that voltage-sensitive sodium channels are activated, setting off the propagation of an action
potential. The concomitant entry of Ca
2+ ions provides an additional physiological signal (Pankratov
and Lalo 2014).
Because of its physiological and historical importance (it is the first pharmacological receptor to
ever have been isolated), the functional properties of the nAChR receptor and the mode of action of a
large variety of its ligands have been studied in great details (for recent reviews, see e.g. Corringer et al.
2012; Sine 2012; Taly et al. 2014; Auerbach 2015; Changeux et al. 2015; Nemecz et al. 2016, and
references therein). For the sake of the present discussion, it will be sufficient to mention the following
(Scheme 1.1).
Fig. 1.25 Overview of structural changes in the BR photocycle. According to Neutze and colleagues
(Wickstrand et al. 2015), two major conformations are sufficient to understand the mechanism of proton
pumping by BR: (i) the resting BR state in which water 402 forms hydrogen bonds to the Schiff base,
Asp85, and Asp212 and (ii) the relaxed illuminated state, in which these bonds are disrupted and helix C
moves toward helix G (B). These conformational changes set the stage for proton transport from the Schiff
base to Asp85. A larger-scale displacement of helix F is however needed to facilitate reprotonation of the
retinal from the cytoplasm (A). To illustrate helix movements, the resting-state structures of helices C and
F are overlaid on the intermediate state conformations (states L/M 1 , red; states M 2 /N, yellow) as
semitransparent purple helices. Helices A and B have been removed from the figure for clarity (Adapted
from Wickstrand et al. 2015).
36
1 Membrane Proteins and Their Natural Environment
The Nicotinic Acetylcholine Receptor
The nicotinic acetylcholine receptor (nAChR) is present in the postsynaptic membrane at neuromuscular junctions and other synapses, including in the central nervous system (for recent reviews,
see e.g. Changeux and Edelstein 2005; Changeux 2012; Corringer et al. 2012; Sine 2012; Cecchini
and Changeux 2015). Upon binding the neurotransmitter acetylcholine (ACh) released in the synaptic
cleft by the nerve terminal, it opens a TM cation-specific channel. As briefly mentioned above (§ 1.3),
the net entry of positive charges that results, mainly due to Na
+ ions, depolarizes the membrane to the
point that voltage-sensitive sodium channels are activated, setting off the propagation of an action
potential. The concomitant entry of Ca
2+ ions provides an additional physiological signal (Pankratov
and Lalo 2014).
Because of its physiological and historical importance (it is the first pharmacological receptor to
ever have been isolated), the functional properties of the nAChR receptor and the mode of action of a
large variety of its ligands have been studied in great details (for recent reviews, see e.g. Corringer et al.
2012; Sine 2012; Taly et al. 2014; Auerbach 2015; Changeux et al. 2015; Nemecz et al. 2016, and
references therein). For the sake of the present discussion, it will be sufficient to mention the following
(Scheme 1.1).
Fig. 1.25 Overview of structural changes in the BR photocycle. According to Neutze and colleagues
(Wickstrand et al. 2015), two major conformations are sufficient to understand the mechanism of proton
pumping by BR: (i) the resting BR state in which water 402 forms hydrogen bonds to the Schiff base,
Asp85, and Asp212 and (ii) the relaxed illuminated state, in which these bonds are disrupted and helix C
moves toward helix G (B). These conformational changes set the stage for proton transport from the Schiff
base to Asp85. A larger-scale displacement of helix F is however needed to facilitate reprotonation of the
retinal from the cytoplasm (A). To illustrate helix movements, the resting-state structures of helices C and
F are overlaid on the intermediate state conformations (states L/M 1 , red; states M 2 /N, yellow) as
semitransparent purple helices. Helices A and B have been removed from the figure for clarity (Adapted
from Wickstrand et al. 2015).
36
1 Membrane Proteins and Their Natural Environment