LYPD6 (LY6/PLAUR domain containing 6) is a GPI-anchored three-finger protein that functions as a negative allosteric modulator of nicotinic acetylcholine receptors (nAChRs) in the brain 1. The protein specifically inhibits α3β4 and α7 nAChR currents with IC50 values of approximately 35 μM and 10 μM, respectively, reducing maximal current amplitude by 30-50% without affecting ACh binding affinity 1. LYPD6 is synaptically enriched and forms direct protein complexes with multiple nAChR subtypes in human brain extracts 2. Functionally, LYPD6 inhibits nicotine-induced calcium influx and attenuates nicotine-evoked hippocampal currents 21. The protein suppresses long-term potentiation in hippocampal slices, similar to α-bungarotoxin, indicating its role in synaptic plasticity regulation 1. Loss of Lypd6 in knockout mice results in reduced anxiety-like behavior and enhanced nicotine responses, with increased nicotine-evoked currents in dorsal raphe neurons 3. Additionally, LYPD6 acts as a positive regulator of Wnt/β-catenin signaling through interactions with the coreceptor LRP6 via its NxI motif 4. The protein is upregulated by perinatal nicotine exposure, suggesting developmental regulation of cholinergic signaling 2.