Abstract
Endocannabinoids are amphiphilic molecules that play crucial neurophysiological functions acting as lipid messengers. Antagonists and knockdown of the classical CB1 and CB2 cannabinoid receptors do not completely abolish many endocannabinoid activities, supporting the idea of a mechanism independent of receptors whose mode of action remains unclear. Here we combine gramicidin A (gA) single channel recordings and membrane capacitance measurements to investigate the lipid bilayer-modifying activity of endocannabinoids. Single channel recordings show that the incorporation of endocannabinoids into lipid bilayers reduces the free energy necessary for gramicidin channels to transit from the monomeric to the dimeric conformation. Membrane capacitance demonstrates that the endocannabinoid anandamide has limited effects on the overall structure of the lipid bilayers. Our results associated with the theory of membrane elastic deformation reveal that the action of endocannabinoids on membrane proteins can involve local adjustments of the lipid/protein hydrophobic interface. The current findings shed new light on the receptor-independent mode of action of endocannabinoids on membrane proteins, with important implications towards their neurobiological function.
Highlights
Consonance, a common mechanism arising from changes in lipid bilayer properties that modifies the energy of hydrophobic coupling between protein and their host bilayer could be hypothesized
The insertion of a membrane protein into the hydrophobic environment of the lipid bilayer is associated with an energy cost, the bilayer deformation energy (ΔGd0ef), which is related to the adjustments of the lipid bilayer to the membrane protein hydrophobic portion
To test the hypothesis that endocannabinoids are bilayer-modifying amphiphiles, we first measured the effects of AEA on the single channel activity of gramicidin A channels
Summary
Consonance, a common mechanism arising from changes in lipid bilayer properties that modifies the energy of hydrophobic coupling between protein and their host bilayer could be hypothesized. Tdlehsseotnhfracetoecnehtnareinbrggueytitochonessptfhfrooyrmsitchtohe-eccohmneemfmoircbmaralanptieroonppraeolrtctehiienasn(ogΔfetGohpIfe→raoltIiemIpinie)dmabnbidlraatynheeer as elasticity, thickness, and intrinsic curvature, may alter the conformational distribution of membrane proteins by changing ΔGIb→ilaIyIer. Here we combined single channel gramicidin A recordings and membrane capacitance measurements to study the bilayer-modifying properties of endocannabinoids. Membrane capacitance results show that the insertion of endocannabinoids into model phospholipid bilayers has limited effects on the bilayer’ thickness, supporting the idea of local modifications. Together, these data imply on the proposal of a new mode of action for the endocannabinoids, independent of receptors and based on their effects on membrane/protein hydrophobic interface. This membrane-mediated action may serve as a good model for understanding the endocannabinoid’s receptor-independent effects observed in neurobiological and other systems
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