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

In a heterogeneous, asymmetric model brain plasma membrane, serotonin rewires Y4R intramolecular communication pathways in a concentration-dependent manner, with 6 mM and 50 mM producing distinct lipid environments.

• Why it matters: Serotonin-linked changes in membrane composition may underlie how neuropeptide Y4 receptor signaling is altered in metabolic disorder and anxiety, but the molecular mechanism beyond direct binding is unclear.
• What they did: Using 825.9 ns all-atom molecular dynamics simulations at 310 K, the study tracked serotonin partitioning, selective lipid reorganization, and PP binding and Y4R activation, then applied weighted implementation of suboptimal paths analysis.
• The result: Without serotonin, Y4R preferentially associates with anionic lipids; serotonin localizes at the lipid-water interface, and at 6 mM contacts phosphocholine depleted from Y4R while at 50 mM phosphatidylinositol 4,5 bisphosphate dominates both microenvironments. These lipid changes align with altered communication between PP binding and activation-associated Y4R residues, informing membrane-targeted pharmacology.

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