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Gene Review

nAChRalpha3  -  nicotinic Acetylcholine Receptor alpha3

Drosophila melanogaster

Synonyms: Acr7E, CG2302, D[a3], Da3, Dalpha3, ...
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High impact information on nAcRalpha-7E

  • The deduced amino acid sequence displays high homology to the ALS protein and shares structural features with ligand binding nAChR alpha-subunits [1].
  • The analysis showed that the first 4 exons and the last exon of all muscle and brain nAChR subunit genes have the same boundaries, with the exception of a nAChR-related gene in Drosophila [2].
  • Although mutations of Thr77 in loop D of the beta2 subunit resulted in a barely detectable effect on the imidacloprid concentration-response curve for the alpha4beta2 nAChR, T77R;E79V double mutations shifted the curve dramatically to higher affinity binding of imidacloprid [3].
  • To investigate the mechanism of neonicotinoid selectivity, we have examined the effects of mutations to basic amino acid residues in loop D of the nAChR acetylcholine (ACh) binding site on the interactions with imidacloprid [3].
  • The coplanar system between the electronegative tip and guanidine-amidine moiety extends the conjugation and facilitates negative charge (delta(-)) flow toward the tip, thereby enhancing interaction with the proposed cationic subsite such as lysine or arginine in the Drosophila nAChR [4].

Biological context of nAcRalpha-7E

  • We have identified the nAChR gene family from the genome of the malaria mosquito vector, Anopheles gambiae, to be the second complete insect nAChR gene family described following that of Drosophila melanogaster [5].
  • The epsilon subunit gene spans 4.3 kilobases and contains 12 exons; it has the same structure as the gamma and delta nAChR genes [2].
  • These imidazopyrimidines with a wide range of N-substituents were found to inhibit [3H]IMI binding to the Drosophila or Musca nAChR by 50% (IC50) at 0.7-38 nM [6].
  • Sequence analysis has identified an open reading frame of 509 amino acids with features typical of nAChR subunits [7].
  • In D. melanogaster, three new nAChR a subunits have been cloned, one of which shows multiple variant transcripts arising from alternative splicing and A-to-I pre-mRNA editing [8].

Anatomical context of nAcRalpha-7E

  • Immunohistochemical studies revealed that Dalpha3 is co-distributed with the beta-subunit ARD in synaptic neuropil regions of the optic lobe [9].
  • This compound (unlabeled) has an IC50 of 8 nM for [3H]-IMI binding in Drosophila head membranes, and the 125I-labeled photoaffinity probe labels only a 66 kDa protein(s) at a specific site inhibited by (-)-nicotine, consistent with the insecticide-binding subunit of the nAChR [6].
  • The vertebrate nAChR, assembled from five homologous subunits, penetrates the synaptic membrane [10].

Associations of nAcRalpha-7E with chemical compounds

  • Likewise, T77K;E79R and T77N;E79R double mutations in the Dalpha2beta2 nAChR also resulted in a shift to a higher affinity for imidacloprid, which exceeded that observed for a single mutation of Thr77 to basic residues [3].
  • Reverse transcription-polymerase chain reaction analysis shows that RNA A-to-I editing sites conserved between Dalpha6 of Drosophila and alpha7-2 of the tobacco budworm, Heliothis virescens, are not shared with the equivalent nAChR subunit of Anopheles [5].
  • We propose that neonicotinoids with a protonated N-unsubstituted imine or equivalent substituent recognize the anionic subsite of the mammalian alpha4beta2 nAChR whereas the negatively charged (delta(-)) tip of the neonicotinoid insecticides interacts with a putative cationic subsite of the insect nAChR [11].
  • With the Drosophila nAChR assay, the N-methyl compounds N-methyl-imidacloprid and thiamethoxam are activated 4.5-29-fold by CYP3 A4 whereas nine other neo-nicotinoids are not changed in potency [12].
  • This study clearly showed that nitroimines, nitromethylenes, and cyanoimines are more selective to Drosophila nAChR and safe for human being, whereas N-substituted imines have affinity to mammalian receptor [13].

Analytical, diagnostic and therapeutic context of nAcRalpha-7E

  • Here we report the molecular cloning, heterologous expression and characterization of this putative Drosophila nAChR subunit (Dbeta3) [14].
  • The genes coding for the beta and epsilon subunits of the mouse muscle nicotinic acetylcholine receptor (nAChR) were mapped by Southern blot analysis, and the entire loci for both genes cloned [2].
  • The insect nAChR is the primary target site for the neonicotinoid insecticides, thereby providing an incentive to explore its functional architecture with neonicotinoid radioligands, photoaffinity probes and affinity chromatography matrices [10].
  • This new preparation, in which whole-cell recordings and pharmacology can be combined with genetic approaches, will be critical in understanding the contribution of nAChR-mediated fast synaptic transmission to cellular plasticity in the neural circuits underlying olfactory associative learning [15].


  1. Heterogeneity of Drosophila nicotinic acetylcholine receptors: SAD, a novel developmentally regulated alpha-subunit. Sawruk, E., Schloss, P., Betz, H., Schmitt, B. EMBO J. (1990) [Pubmed]
  2. Isolation and characterization of the beta and epsilon subunit genes of mouse muscle acetylcholine receptor. Buonanno, A., Mudd, J., Merlie, J.P. J. Biol. Chem. (1989) [Pubmed]
  3. Role in the selectivity of neonicotinoids of insect-specific basic residues in loop d of the nicotinic acetylcholine receptor agonist binding site. Shimomura, M., Yokota, M., Ihara, M., Akamatsu, M., Sattelle, D.B., Matsuda, K. Mol. Pharmacol. (2006) [Pubmed]
  4. The neonicotinoid electronegative pharmacophore plays the crucial role in the high affinity and selectivity for the Drosophila nicotinic receptor: an anomaly for the nicotinoid cation--pi interaction model. Tomizawa, M., Zhang, N., Durkin, K.A., Olmstead, M.M., Casida, J.E. Biochemistry (2003) [Pubmed]
  5. The nicotinic acetylcholine receptor gene family of the malaria mosquito, Anopheles gambiae. Jones, A.K., Grauso, M., Sattelle, D.B. Genomics (2005) [Pubmed]
  6. Synthesis of a novel [125I]neonicotinoid photoaffinity probe for the Drosophila nicotinic acetylcholine receptor. Latli, B., Tomizawa, M., Casida, J.E. Bioconjug. Chem. (1997) [Pubmed]
  7. Cloning, heterologous expression and co-assembly of Mpbeta1, a nicotinic acetylcholine receptor subunit from the aphid Myzus persicae. Huang, Y., Williamson, M.S., Devonshire, A.L., Windass, J.D., Lansdell, S.J., Millar, N.S. Neurosci. Lett. (2000) [Pubmed]
  8. Functional genomics of ionotropic acetylcholine receptors in Caenorhabditis elegans and Drosophila melanogaster. Sattelle, D.B., Culetto, E., Grauso, M., Raymond, V., Franks, C.J., Towers, P. Novartis Found. Symp. (2002) [Pubmed]
  9. Neuronal nicotinic acetylcholine receptors of Drosophila melanogaster: the alpha-subunit dalpha3 and the beta-type subunit ARD co-assemble within the same receptor complex. Chamaon, K., Schulz, R., Smalla, K.H., Seidel, B., Gundelfinger, E.D. FEBS Lett. (2000) [Pubmed]
  10. Structure and diversity of insect nicotinic acetylcholine receptors. Tomizawa, M., Casida, J.E. Pest Manag. Sci. (2001) [Pubmed]
  11. Structural features of azidopyridinyl neonicotinoid probes conferring high affinity and selectivity for mammalian alpha4beta2 and Drosophila nicotinic receptors. Zhang, N., Tomizawa, M., Casida, J.E. J. Med. Chem. (2002) [Pubmed]
  12. Neo-nicotinoid metabolic activation and inactivation established with coupled nicotinic receptor-CYP3A4 and -aldehyde oxidase systems. Honda, H., Tomizawa, M., Casida, J.E. Toxicol. Lett. (2006) [Pubmed]
  13. Quantitative structure-activity relationship study on some azidopyridinyl neonicotinoid insecticides for their selective affinity towards the drosophila nicotinic receptor over mammalian alpha4beta2 receptor using electrotopological state atom index. Debnath, B., Gayen, S., Naskar, S.K., Roy, K., Jha, T. Drug design and discovery. (2003) [Pubmed]
  14. Dbeta3, an atypical nicotinic acetylcholine receptor subunit from Drosophila : molecular cloning, heterologous expression and coassembly. Lansdell, S.J., Millar, N.S. J. Neurochem. (2002) [Pubmed]
  15. Cholinergic synaptic transmission in adult Drosophila Kenyon cells in situ. Gu, H., O'Dowd, D.K. J. Neurosci. (2006) [Pubmed]
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