A publication in Amino Acids by researchers from UPF, CRG and other centers provides the first in vivo evidence of the involvement of the CHRNA5/A3/B4 gene cluster in nicotine addiction. It happens through modifying the activity of brain regions responsible for the balance between the rewarding and the aversive properties of this drug. CHRNA5/A3/B4 codes for the nicotinic acetylcholine receptor subunits A5, A3 and B4. Together they form the ligand-gated pentameric ion channels that modulate key physiological processes ranging from neurotransmission to cancer signaling. These receptors are activated by the neurotransmitter, acetylcholine, and the tobacco alkaloid, nicotine. Recently, the gene cluster received interest after a succession of linkage analyses and association studies identified multiple single-nucleotide polymorphisms in these genes that are associated with an increased risk for nicotine dependence and lung cancer.
To see the in vivo effects of the cluster, a transgenic mouse overexpressing the human CHRNA5/A3/B4 cluster was generated using a bacterial artificial chromosome. Transgenic mice showed increased functional receptors in brain regions where these subunits are highly expressed under normal physiological conditions. Moreover, they exhibited increased sensitivity to the pharmacological effects of nicotine. Transgenic mice also showed increased acquisition of nicotine self-administration.
Gallego X, Molas S, Amador-Arjona A, Marks MJ, Robles N, Murtra P, Armengol L, Fernández-Montes RD, Gratacòs M, Pumarola M, Cabrera R, Maldonado R, Sabrià J, Estivill X, Dierssen M. Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects. Amino Acids. 2011 Nov 19
© 2010 Oncogene: Structure of the Nicotinic acetylcholine receptor (nAChR). (a) Schematic representation illustrating the pentameric arrangement of subunits in an assembled nAChR. (b) Conserved domains of a nAChR subunit including the amino (N) and carboxy (C) terminals, transmembrane segments (M1–M4) and the intracellular loop. (c) Assembly of heteromeric and homomeric nAChR subtypes. Individual nAChR subunits are represented as colored circles, with diamonds representing ligand-binding sites. Pentagons in the center of each pentamer represent the pore region.