protein (high risk variant) in the nicotinic acetylcholine receptor lowers Ca2+permeability and increases short-term desensitization in (α4β2)α5, but does not alter the receptor sensitivity to activation (Kuryatov et al., 2011). The high sensitivity to activation and desensitization of (α4β2)α5 nicotine acetylcholine receptors by nicotine results in a narrow concentration range in which activation and desensitization curves overlap at nicotine concentrations typically sustained in smokers. It is predicted that smokers would desensitize most of these receptors while permitting a smoldering activation of the remainder of the receptors. In addition, the α5 nicotinic receptor subunit is expressed in the brain regions that are important in the pathways relevant to the development of dependence. Finally, this key α5 gene variant is associated with a dorsal anterior cingulate-ventral striatum/extended amygdala circuit, and the “risk allele” decreases the intrinsic resting functional connectivity strength in this circuit (Hong et al., 2010). Importantly, this effect is observed in nonsmokers and it appears to represent a trait circuitry biomarker.
