Lynx2 modulators of nicotinic receptors implicated in anxiety. Homo sapiens

Anxiety disorders are prevalent and under treated, stemming from a complex interaction of psychological, genetic, learning, and environmental factors. Nicotinic acetylcholine receptors have been implicated in anxiety. They are modulated by the prototoxins Lynx1 and Lynx2, which contain a three-fingered receptor-binding toxin motif). Lynx genes have been shown to influence a variety of different neuronal circuits, brain regions which are related to specific diseases. Lynx2 inhibits a4b2 receptor activity and decreases the receptor's cell surface expression. In mice, the Lynx2 gene is expressed within anxiety-related neural circuitry and is functionally associated with anxiety -like behavior. This study investigates the relationship between human Lynx2/lypd1 gene polymorphisms and anxiety levels by DNA sequencing and self reporting questionnaires used in clinical assessments, such as the STICSA and STAI tests of anxiety. We found that the presence of an unreported single nucleotide polymorphism (SNP), Lynx2/lypd1 Q61H, in the human mature protein-coding region of Lynx2 is associated with anxiety scores similar to clinically diagnosed generalized anxiety and panic disorder. Using atomic force microscopy (AFM), it has been found that this Lynx2 mutation alters binding affinity to a7-nAChRs, which may underly the influence of Lynx2 on anxiety in carriers. This work can aid in the understanding and detection of anxiety and other related nervous system disorders.