NAChRs receptors

Two groups of acetylcholine receptors have been identified in humans the muscarinic (mAChR) and nicotinic (nAChR) receptors, named after their artificial activating ligands, muscarine and nicotine. These receptors function through entirely different mechanisms, either as a slow acting metabotropic G-protein-coupled receptor (mAChR) or fast acting ion-channel type receptor (nAChR). 

Figure 14.14. Example of pharmacophoric element selection for molecular modeling of nicotine. Pharmacophoric elements A and B are nitrogens and element C is on the nAChR receptor with which element B would optimally connect. Carbon, green nitrogen, light blue hydrogen attached to the basic nitrogen, white putative nAChR binding site, dark blue.

Acetylcholine. Acetylcholiae (ACh) (1) is a crystalliae material that is very soluble ia water and alcohol. ACh, synthesized by the enzyme choline acetyltransferase (3), iateracts with two main classes of receptor ia mammals muscarinic (mAChR), defiaed oa the basis of the agonist activity of the alkaloid muscarine (4), and nicotinic (nAChR), based on the agonist activity of nicotine (5) (Table 1). m AChRs are GPCRs (21) n AChRs are LGICs (22). 

A systematic nomenclature for nAChRs has yet to evolve. An N nomenclature describes receptors present ia muscle as N. These are activated by phenyltrimethylammonium (PTMA) (15) and blocked by t5 -tubocurariae (16) and a-bungarotoxiu (a-BgT) (17). N2 receptors are present ia ganglia and are activated by l,l-dimethyl-4-phenylpipera2inium (DMPP) (18) and blocked by trimethaphan (19) and bis-quatemary agents, with hexamethonium (20) being the most potent. 

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)... 

The nicotinic receptor (nAChR) comprises a family of receptor subtypes that respond to the neurotransmitter acetylcholine (ACh) and the tobacco alkaloid nicotine. 

Nature has created a diverse array of plant and animal toxins that act at mammalian muscle and ganglionic nAChRs or invertebrate nAChRs because the critical physiological functions of these receptors make them prime targets for defensive or predatory strategies. More recently, the perceived validity of neuronal nAChR as therapeutic targets has prompted the generation of new synthetic ligands. Examples are listed in Table 1. 

Nicotinic Receptors. Table 1 Some drugs that act at nAChRs... 

The open channel has in most cases a selective permeability, allowing a restricted class of ions to flow,for example Na+, K+, Ca++ or Cl- and, accordingly, these channels are called Na+-channels, K+-channels, Ca -channels and Cr-channels. In contrast, cation-permeable channels with little selectivity reject all anions but discriminate little among small cations. Little is known about the structures and functions of these non-selective cation channels [1], and so far only one of them, the nicotinic acetylcholine receptor (nAChR, see Nicotinic Receptors), has been characterized in depth [2, 3]. The nAChR is a ligand-gated channel (see below) that does not select well among cations the channel is even permeable to choline, glycine ethylester and tris buffer cations. A number of other plasma... 

The nAChR is cylindrical with a mean diameter of about 6.5 nm (Fig. 1). All five rod-shaped subunits span the membrane. The receptor protrades by <6 nm on the synaptic side of the membrane and by <2 nm on the cytosolic side [2]. The pore of the channel is along its symmetry axis and includes an extracellular entrance domain, a transmembrane domain and a cytosolic entrance domain. The diameter of the extracellular entrance domain is <2.5 nm and it becomes narrower at the transmembrane domain. The... 

Non-selective Cation Channels. Figure 1 The nicotinic acetylcholine receptor (nAChR) is localized within the cell membrane above the cell membrane is the synaptic cleft, below the cytoplasm. Drawing of the closed (left) and open (right) nAChR showing acetylcholine (ACh) binding and cation movement. Dimensions of the receptor were taken from references [2, 3]. 

In their search for new hgands with a very high binding affinity for the nicotinic acetylchohne receptor (nAChR), potentially useful in positron emission tomography (PET) when radiolabeled with [ F], Horti et al. described the synthesis of BOC-protected 5-(azetidin-2-ylmethoxy)-2-chloro-6 -fluoro-3,3 -bipyridine via a sequential classical heating and microwave irradiation of (2-fluoro-5-pyridinyl)(trimethyl)stannane with f-butyl 2- [(6-chloro-5-... 

Neonicotinoids are potent broad-spectrum insecticides that exhibit contact, stomach and systemic activity. Acetamiprid, imidacloprid, nitenpyram, thiamethoxam and thiacloprid are representatives of the neonicotinoid insecticides (Figure 1). The mechanism of action is similar to that of nicotine, acting on the central nervous system causing irreversible blocking of postsynaptic nicotinic acetylcholine receptors (nAChR). Neonicotinoid insecticides are often categorized as antagonists of the... 

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... 

The regions involved in the cation vs. anion selectivity are not well defined, as they are for the nAChR. However, in contrast to the nAChR, the residues within the pore contribute to the selectivity, as receptors formed from fully edited AMPA or kainate receptors (e.g., having an R at the Q/R site) are also permeable to chloride. 

Assume the assembly of nicotine acetylcholine receptor (nAChR) subunits is completely permissive. How many dilferent receptors can be assembled in a cell expressing 03, p2, and (>4 Group the... 

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