Beyond Direct Binding: Serotonin Rewires Model Brain Plasma Membrane-Mediated Communication Pathways in Y4R

Serotonin, an endogenous neurotransmitter, modulates pancreatic polypeptide (PP) recognition by the neuropeptide Y4 receptor (Y4R), a mechanism relevant to altered serotonergic signaling associated with metabolic disorder and anxiety. Although recent experiment demonstrates serotonin modulated PP dissociation kinetics of Y4R through membrane allostery, the molecular mechanism of serotonin induced lipidomic reorganization of the brain plasma membrane (BPM) relevant for Y4R activation is unknown. To this end, a total of 825.9 ns long all atom molecular dynamics simulations at 310 K elucidate the concentration-dependent coupling between serotonin partitioning, selective lipid reorganization, and PP binding and Y4R activation relevant intra-receptor communication in a heterogeneous, asymmetric model BPM. In the absence of serotonin, Y4R preferentially associates with the anionic lipids. Serotonin preferentially localizes at the lipid water interface over the PP binding and activation-associated regions of Y4R. At 6 mM, serotonin preferentially contacts phosphocholine species depleted from Y4R, whereas at 50 mM, phosphatidylinositol 4,5 bisphosphate dominates both microenvironments. These changes align with the selective remodeling of lipid networks, enhanced lipid chain ordering, and modest bilayer compaction. Weighted implementation of suboptimal paths analysis reveals concentration-dependent reorganization of communication pathways between experimentally implicated PP binding and activation associated Y4R residues. Collectively, these findings connects serotonin dependent selective lipid redistribution to altered intramolecular communication between Y4R residues associated with PP binding and G-protein coupling, and provide a framework for future experiments investigating membrane-mediated neuromodulation and neuronal signaling. These findings provide a basis for exploring lipid-targeted pharmacology as a complementary strategy to modulate GPCR allostery by altering membrane composition rather than directly targeting the receptor.