Ligand binding nicotinic receptors

F. Liang, H.A. Navarro, P. Abraham, P. Kotian, Y.S. Ding, J.S. Fowler, N.D. Volkow, M.J. Kuhar, F.l. Carroll, Synthesis and nicotinic acetylcholine receptor binding properties of exo-2-(2 -fluoro-5 -pyridinyl)-7-azabicyclo-[2.2.1 (heptane A new positron emission tomography ligand for nicotinic receptors, J. Med. Chem. 40 (1997) 2293-2295. 

Dolle, F., Dolci, L., Valette, H., Hinnen, F., Vaufrey, F., Guenther, I., Fuseau, C., Coulon, C., Bottlaender, M., Crouzel, C. Synthesis and Nicotinic Acetylcholine Receptor in Vivo Binding Properties of 2-Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine A New Positron Emission Tomography Ligand for Nicotinic Receptors. J. Med. Chem. 1999, 42, 2251-2259. 

Carroll FI, Lee JR, Navarro HA, Ma W, Biieaddy LE, Abraham P, Damaj MI, Martin BR (2002) Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2, 3 -disubstituted 5 -pyiidinyl)-7-azabicyclo[2.2.1]heptanes epibatidine analogues a new positron emission tomography ligand for nicotinic receptors. J Med Chem 45(21) 4755 761... 

Thermodynamically it would be expected that a ligand may not have identical affinity for both receptor conformations. This was an assumption in early formulations of conformational selection. For example, differential affinity for protein conformations was proposed for oxygen binding to hemoglobin [17] and for choline derivatives and nicotinic receptors [18]. Furthermore, assume that these conformations exist in an equilibrium defined by an allosteric constant L (defined as [Ra]/[R-i]) and that a ligand [A] has affinity for both conformations defined by equilibrium association constants Ka and aKa, respectively, for the inactive and active states ... 

Brejc, K., van Dijk, W. J., Klassen, R. V., Schuurmans, M., van der Oost, J., Smit, A. B., and Sixma, T. K., Crystal structures of an ACh-binding protein reveal the ligand-binding domain of nicotinic receptors, Nature, 411, 269-276, 2001. 

In this scheme, M <1 and K equilibrium constants. Direct binding experiments have confirmed the generality of this scheme for nicotinic receptors. Thus, distinct conformational states govern the different temporal responses that ensue upon addition of a ligand to the nicotinic receptor. No direct energy input or covalent modification of the receptor channel is required. 

Structure of fluorescent probes that have been used to study ligand binding to the Torpedo nicotinic acetylcholine receptor... 

Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Dost J, et al. 2001. Crystal structure of an Ach-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411 269. 

ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411 269-276. 

Sine SM, Wang HL, Bren NH. 2002. Lysine scanning mutagenesis delinates structural model of the nicotinic receptor ligand binding domain. J Biol Chem 277 29210-292... 

Sabey K, Paradiso K, Zhang J, Steinbach JH (1999) Ligand binding and activation of rat nicotinic a4 32 receptors stably expressed in HEK293 cells. Mol Pharmacol 55 58-66... 

Ion channels (center). These receptors contain ligand-gated ion channels. Binding of the signaling substance opens the channels for ions such as Na, Ca, and Cl . This mechanism is mainly used by neurotransmitters such as acetylcholine (nicotinic receptor see p.224) and GABA (A receptor see p.354). 

Acetylcholine (ACh) is an example of an endogenous neurotransmitter that binds to more than one receptor type, the nicotinic acetylcholine receptor (nAChR) which preferentially binds nicotine and the muscarinic receptor which binds muscarine, a mushroom alkaloid. The latter is a G protein-coupled receptor while the nACh receptor is an excitatory ligand-gated ion channel that transports Na-i- ions. Nicotinic cholinergic receptors are found in the CNS, autonomic ganglia, and at the neuromuscular junction of skeletal muscles. They are a possible target for anaesthetics. 

Sine SM. The nicotinic receptor ligand binding domain. J Neurobiol. 2002 53 431-446. 

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