Heteromeric nicotinic receptors

Keyser KT, Britto ERG, Schoepfer R, Whiting P Cooper J, Conroy W, Brozozowska-Prechtl A, Karten HJ, Lindstrom J (1993) Three subtypes of a-bungarotoxin-sensitive nicotinic acetylcholine receptors are expressed in chick brain. J Neurosci 13 442-452 Khiroug S, Harkness PC, Lamb PW, Sudweeks S, Khiroug L, Millar NS, Yakel JL (2002) Rat nicotinic ACh receptor al and fil subunits co-assemble to form functional heteromeric nicotinic receptor channels. J Physiol 540 425 34... 

Finally, changes in extracellular calcium (in the low millimolar range) can modulate nicotinic responses. Increases in calcium concentration strongly enhance macroscopic responses of either native or recombinant heteromeric nicotinic receptors to low ACh concentrations, decreasing the BC value of ACh and increasing the Hill slope of the curve (133, 140, 160, 161). This effect is not seen with muscle embryonic channels (133). In native a7 receptors the modulation has been reported to be biphasic, with potentiation at submillimolar calcium concentrations and depression at higher concentrations (162). The sequence determinants for this effect have... 

Nicotine is an agonist at the nicotinic acetylcholine receptor (nAChR). Activation of this receptor depolarizes target cells (see Ch. 11). nAChRs are composed of five subunits surrounding a central ion-channel pore. Twelve different nicotinic receptor subunits are expressed in the nervous system (a2-oclO and (32—134). Of these, a subset is expressed in the VTA (a3-a7 and P2—134). It is thought that a7 receptors form homomeric receptors a3, a4 and a6 form heteromeric channels with 02 or 04 and a5 and 03 can associate with other a/0 pairs. Studies in knockout mice implicate several subunits in the ability of nicotine to modulate dopamine neurons (a4, a6, a7, 02, 03) but... 

Ion channels consist of homo-or heteromeric complexes numbering between three (P2X) and eight (Kirs) subunits. Examples of these are the GABA /benzodiazepine and NMDA/ glycine receptor, neuronal nicotinic receptors (nAChR), and P2X receptors. 

A worm-eating species, C. imperialis, produces a-conotoxin Iml, which is an effective antagonist of homomeric-type neuronal nicotinic receptors, such as rat a7 or a9 (reported IC50 values of 0.22 and 1.8 (jM, respectively). This commercially available 12 amino acid amidated peptide is a very weak blocker of mouse muscle receptors (IC50 = 51 jtiM) and is ineffective at 5 fiM on heteromeric rat neuronal receptors (259). 

One class of neuronal nicotinic receptors exists as a heteromeric pentamer composed of a (02-0 ) and 3 ( 32- 34) subunits (25,26,27)—for example, 04 3 virith a stoichiometry of tviro 04 and three p3 subunits. Another class of functional homomeric nicotinic receptors is composed of 07 through aio subunits. The diversity of the subunits and the pentameric structure suggest that a large number of nicotinic receptor subtypes may exist. 

Homology Modeling of nAChRs has Assisted in the Identification of Key Amino Acid Residues Involved in the Selective Interactions with Neonicotinoids of Heteromeric Nicotinic Acetylcholine Receptors... 

Figure 3. Schematic representation of nicotinic acetylcholine receptors. Side (A) and top (B) views ofheteromeric and homomeric nicotinic receptors. Loops A-F forming the agonist binding site of heteromeric receptors and key amino acid residues that have been shown to contribute to the agonist binding are also illustrated in B. Abbreviation ACh, acetylcholine. Reproduced from Ref. 10 with permission of Elsevier. (See page 2 of color insert.)...

The nAChR subtypes vary in response to pharmacological manipulation. The a7 receptors have a low affinity for nicotine and are sensitive to a-bungarotoxin (a-BTX) antagonism, whereas the heteromeric nAChRs are not.14 The p2 containing (p2 asterisk denotes the presence of additional subunits) nAChRs have the highest affinity for nicotine binding and some selectivity for antagonism... 

Figure 2.1 Diagram of nicotinic acetylcholine receptor (nAChR) structure. A top view of (A) an a7 nAChR and (B) a p2 nAChR shows that homomeric and heteromeric classes of nAChRs are both pentameric in structure. Each subunit is made up of four transmembrane domains with the M2 domain making up the ion pore. (C) A side view of the four transmembrane regions shows the N terminus, C terminus, and large M3-M4 intracellular loop that make up each nAChR subunit. The extracellular loops are available for binding to ligands and the intracellular loop is available for regulation of the nAChR by intracellular signaling proteins.

The earliest studies that attempted to determine whether ct4 subunits formed functional receptors in Xenopus oocytes established that function was obtained only if the oocytes were also injected with either P2 or P4 cDNA, thereby establishing the concept of heteromeric neuronal nAChRs (Deneris et al. 1988, Connolly et al. 1992). The oc4p2 nAChR has been studied extensively because (i) it seems to be the most widely expressed nAChR subtype (ii) it was considered, until recently, to be the highest affinity nAChR and (iii) the number and function of these receptors are altered by chronic nicotine treaUnent. 

Figure 6.2. Diagrammatic representation of the 5-HT3 receptor. The 5-HT3 receptor is distinct from the other 5-HT receptor subtypes, in that it is a ligand gated ion channel that is permeable to sodium and potassium. The 5-HT3 receptor is structurally similar to the nicotinic acetylcholine receptor and is composed of five sub-units. Two sub-units have been cloned, 5-HT3A and 5-HT35, and homomeric (5-HT3A) and heteromeric (5-HT3a/5-HT3b) forms of the receptor have both been...

The a4p2 nAChR is the predominant heteromeric receptor in the brain, binds nicotine and other nicotinic agonists, e.g. cytisine and epibatidine. As a principal nicotinic AChR is more ubiquitous and is predominant in cortex, striatum, superior colliculus, lateral geniculate nucleus and cerebellum. When activated it facilitates excitatory inputs and is present very early in the developing brain in various brain regions. 

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