Molecular rheology of neuronal membranes explored using a molecular rotor: Implications for receptor function

• Fluorescent molecular rotors are characterized by an excited state process dependent on intramolecular rotational motion.
• BODIPY-C12 allows measurement of membrane viscosity by its characteristic viscosity-sensitive fluorescence depolarization.
• Specific agonist binding by the serotonin1A receptor exhibits close correlation with hippocampal membrane viscosity.
• The role of membrane fluidity in GPCR function has important physiological implications

The role of membrane cholesterol as a crucial regulator in the structure and function of membrane proteins and receptors is well documented. However, there is a lack of consensus on the mechanism for such regulation. We have previously shown that the function of an important neuronal receptor, the serotonin1A receptor, is modulated by cholesterol in hippocampal membranes. With an overall objective of addressing the role of membrane physical properties in receptor function, we measured the viscosity of hippocampal membranes of varying cholesterol content using a meso-substituted fluorophore (BODIPY-C12) based on the BODIPY probe. BODIPY-C12 acts as a fluorescent molecular rotor and allows measurement of hippocampal membrane viscosity through its characteristic viscosity-sensitive fluorescence depolarization. A striking feature of our results is that specific agonist binding by the serotonin1A receptor exhibits close correlation with hippocampal membrane viscosity, implying the importance of global membrane properties in receptor function. We envision that our results are important in understanding GPCR regulation by the membrane environment, and is relevant in the context of diseases in which GPCR signaling plays a major role and are characterized by altered membrane fluidity.

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