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In adult mammalian skeletal muscle, the nicotinic acetylcholine receptor (nAChR) is a pentameric complex of two α-subunits in association with single β-, δ-, and epsilon-subunits ( Fig. 13-1 ). These subunits are organized to form a transmembrane pore (a channel), as well as the extracellular binding pockets for acetylcholine and other agonists or antagonists.[17] Each of the two α-subunits has an acetylcholine-binding site. These sites are proteins located in pockets approximately 3.0 nm above the surface membrane at the interfaces of the αH -epsilon and αL -δ subunits.[18]
Figure 13-1
Subunit composition of the nicotinic acetylcholine receptor
(nAChR) in the end-plate surface of adult mammalian muscle. The adult AChR is an
intrinsic membrane protein with five distinct subunits (α2
βδepsilon).
Each subunit contains four helical domains labeled M1 to M4. The M2 domain forms
the channel pore. The upper panel shows a single
α-subunit with its N and C termini on the extracellular surface of the membrane
lipid bilayer. Between the N and C termini, the α-subunit forms four helices
(M1, M2, M3, and M4) that span the membrane bilayer. The lower
panel shows the pentameric structure of the nAChR of adult mammalian muscle.
The N termini of two subunits cooperate to form two distinct binding pockets for
acetylcholine (ACh). These pockets occur at the epsilon-α and the δ-α
subunit interface. The M2 membrane-spanning domain of each subunit lines the ion
channel. The doubly liganded ion channel has permeability equal to that of Na+
and K+
; Ca2+
contributes approximately 2.5% to the total permeability.
(Redrawn from Naguib M, Flood P, McArdle JJ, et al: Advances in neurobiology
of the neuromuscular junction: Implications for the anesthesiologist. Anesthesiology
96:202–231, 2002.)
Functionally, the ion channel of the acetylcholine receptor is closed in the resting state. Simultaneous binding of two acetylcholine molecules to the α-subunits[23] initiates conformational changes that open the channel.[24] [25] [26] On the other hand, it is enough for one molecule of a nondepolarizing neuromuscular blocker (a competitive antagonist) to bind to one subunit to produce a block.[27] Paul and coworkers [28] found a correlation between the ED50 (the dose that produces 50% depression of twitch tension) and the potency of nondepolarizing blockers at the adult nAChR.
Depolarizing neuromuscular blockers such as succinylcholine produce prolonged depolarization of the end-plate region that results in (1) desensitization of nAChR, (2) inactivation of voltage-gated sodium channels at the neuromuscular junction, and (3) increases in potassium permeability in the surrounding membrane (see Chapter 22 for details). [27] The end result is failure of action potential generation, and block ensues. It should be noted that although acetylcholine produces depolarization, under physiologic conditions it results in muscle contraction because it has a very short (few milliseconds) duration of action.[27] Acetylcholine is rapidly hydrolyzed by acetylcholinesterase[29] to acetic acid and choline. Administration of large doses of acetylcholine in experimental animals, though, produces neuromuscular blockade.[27]
The fetal nAChR is a low-conductance channel, in contrast to the high-conductance channel of adult nAChR. Thus, acetylcholine release causes brief activation and a reduced probability of channel opening.[17] The upregulation of nAChRs that is found in states of functional or surgical denervation is characterized by the spreading of predominantly fetal-type nAChRs. These receptors are resistant to nondepolarizing neuromuscular blockers and more sensitive to succinylcholine. [30] When depolarized, the immature isoform has a prolonged open channel time, which exaggerates K+ efflux.[31]
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