Auxin signaling, long established in plants, was considered absent in mammals due to the lack of canonical biosynthetic genes and transport machinery. Yet, gut microbiota-derived indole metabolites, including auxin (IAA), can be taken up by human cells, where they support neuronal development, synaptic plasticity, and neuroprotection. Recent studies have highlighted a novel auxin-cholesterol crosstalk in mammalian systems, mediated by GPR155 (LYCHOS), an orphan lysosomal membrane protein highly expressed in the brain. GPR155 is a polymodal “transceptor” that uniquely combines a GPCR domain with a transporter domain. Aberrant GPR155 expression is linked to several neurological disorders, including Parkinson’s, Alzheimer’s, and Huntington’s diseases, suggesting a broader role in neuronal physiology and pathology. Here, we present the structural characterization of human GPR155, revealing both monomeric and cholesterol-sensitive dimeric states. The transporter domain adopts an inward-open conformation, while the GPCR domain is structurally inactive, with luminal loop 7 occupying the orthosteric pocket. Cholesterol concentration governs dimeric assembly: under low cholesterol, the transporter domain resembles plant PIN transporters and supports auxin transport, whereas high cholesterol promotes a unique dimer stabilized by cholesterol molecules. To further investigate the functionality of GPR155, we performed electrophysiological recordings in a lipid bilayer system to characterize the kinetics of auxin transport. Interestingly, these recordings also revealed voltage-dependent activity of the transceptor. Altogether, these findings will serve as a springboard for understanding the dynamic regulatory mechanism through which cholesterol modulates auxin transport and GPR155 activity. These insights will advance our understanding of cross-species auxin signaling in mammals and enable rational strategies for targeting GPR155 in neurological disorders.
Mansi Sharma (Sun,) studied this question.