Functional implications of the C182F TAAR1 variant identified in patients with schizophrenia

Trace amine-associated receptor 1 (TAAR1) is an emerging pharmaceutical target for treating a variety of neuropsychiatric conditions, with several drug candidates in clinical and preclinical development. Multiple single-nucleotide variants have been associated with neuropsychiatric disorders, and genetic variants may influence the therapeutic outcomes of TAAR1-based therapies. Here, we utilize mutagenesis, functional assays, and computational models to profile schizophrenia-associated TAAR1 variant C182 45.50 F. In cyclic adenosine monophosphate (cAMP) assays, TAAR1 C182 45.50 F demonstrated a complete loss of activity in the homozygous state, and approximately 50% loss in the heterozygous state compared to TAAR1 WT (wild type). Furthermore, the surface expression of homozygous TAAR1 C182 45.50 F was altered, with approximately 40% reduction in surface expression compared to TAAR1 WT. Expression marginally improved in the heterozygous state. Molecular dynamics simulations of the TAAR1 C182 45.50 F model demonstrated increased extracellular loop 2 (ECL2) flexibility, with F182 45.50 forming a stable aromatic cluster (aromatic–aromatic interactions) involving F165 ECL2 and Y172 ECL2 that occludes the orthosteric binding site. The aromatic cluster is further stabilized by a transient salt bridge between E93 3.22 and K97 3.26 . Overall, our study shows the TAAR1 C182 45.50 F variant may disrupt endogenous trace amine signaling via a reduction of cell surface expression and occlusion of endogenous ligand binding; in addition, newly developed TAAR1 therapeutics may be subefficacious in carriers of this variant.