The Muscle nAChR

Molecular cloning has resulted in the identification of the muscle nAChR subunits oq, (3h y, 6, and 8 and the structurally related neuronal a2 to a10 and 32 to 34. The neuronal nAChR subunits a2 to a4 can assemble with 32 or 34 and generate functional heteromeric receptors the a7 to a9... 

Nicotinic receptors (nicotinic acetylcholine receptors, nACHR) exist not only in the membrane of vertebrate skeletal muscle at the synapse between nerve and muscle (muscle-type nAChR) but also at various synapses throughout the brain, mainly at presynaptic positions (neuronal-type nAChR). Whereas the muscle-type nAChR is precisely composed of two a 1-subunits, one (3 -subunit, one y -subunit and one y -subunit (adult)... 

Claude Bernard s early discovery (1856) that curare, the South American arrow poison (woorari), blocked muscle contraction elicited by stimulation of motor neurons, but not that elicited by direct stimulation of the muscle, provided the first demonstration that drugs could be used to study, what we now know are, nAChR-regulated functions. Bernard s early experiment served as the model for Langley s demonstration that the actions of nicotine on skeletal muscle could be blocked by pretreatment with curare (Langley 1880, 1907) and mimicked by pituri, the active... 

Early studies of muscle nAChRs established that the receptor has two agonist binding sites and both must be occupied for efficient channel opening to occur. 

The 1.6 A-resolution crystal structure of the muscle al subunit extracellular domain revealed an unexpected water molecule in the core of the al nAChR subunit, in the vicinity of the transmembrane domain (Dellisanti et al. 2007). This is surrounded by hydrophilic residues that are conserved in nAChR subunits, but absent from the AChBR The water molecule confers flexibility, making the non-optimally... 

The aptamers obtained against the nAChR either are biologically active by themselves and inhibit the muscle-type nAChR activity as cocaine does or are by them biologically inactive and, therefore, protect the receptor against inhibition by cocaine (25). 

For the electrophysiological assay, BCjHl cells that express the muscle-type nAChR are plated in cell culture dishes. 

The adult nicotinic acetylcholine receptor (nAChR) is an intrinsic membrane protein with five distinct subunits (a2B T). A Cartoon of the one of five subunits of the AChR in the end plate surface of adult mammalian muscle. Each subunit contains four helical domains labeled Ml to M4. The 2 domains line the channel pore. B Cartoon of the full nAChR. The N termini of two subunits cooperate to form two distinct binding pockets for acetylcholine (ACh). These pockets occur at the (X-B and the 3-Ct subunit interfaces. 

Table 1 Comparison of the ability of venom-derived (vd-) and recombinant (r-) K-bgt to block the binding of I-a-bgt to the mouse fetal muscle nAChR expressed in QT-6 quail fibroblasts.

At the neuromuscular junction, nicotinic function is enhanced by inhibition of AChE. However, unlike muscle nAChRs, some neuronal nAChRs, particularly those bearing the a7 subunit, recognize both acetylcholine and its metabolite choline as full agonists (Pereira et al., 2002). Therefore, cholinesterase inhibition may not necessarily enhance functions mediated by these nAChRs. In fact, cholinesterase inhibitors do not affect a7 nAChR-mediated synaptic transmission evoked by low-frequency stimulation of cholinergic fibers in chick cUiary ganglia (Zhang et al., 1996). 

Six a-conotoxins have been isolated from C. geographus, two of which target the neuronal nAChRs, suggesting that both muscle and neuronal subtypes are important in prey capture. Often multiple a3/5-conotoxins are found within the venom of one mollusk, although the reason for having multiple toxins targeting one receptor is not clear. 

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