The agonist binding sensitivity and desensitisation kinetics of nicotinic acetylcholine receptors (nAChRs) can be modulated by snake venom neurotoxins and related endogenous small proteins of the uPAR-Ly6 family. We have identified Lypd6, a distantly related member of this family as a modulator of nAChRs in neurons. Transgenic mice overexpressing Lypd6 display behaviors that were indicative of an enhanced cholinergic tone, such as a higher locomotor arousal and hypoalgesia. These mice are also more sensitive to the analgesic effects of nicotine.

In trigeminal ganglia cells Lypd6 selectively enhanced the Ca²⁺-component of nicotine-evoked currents through nAChRs, as evidenced by comparative whole-cell patch clamp recordings and Ca²⁺-imaging. In contrast, a knockdown of Lypd6 expression using siRNAs selectively reduced nicotine-evoked Ca²⁺-currents. Pharmacological experiments with blockers such as alpha-Bungarotoxin or methyllycaconitine revealed that the nAChRs involved in this process are heteromers.

Taken together, Lypd6 seems to constitute a novel modulator of nAChRs that affects receptor function by selectively increasing Ca²⁺-influx through this ion channels.