Influence of the St. John's Wort Extract Ze117 on the Lipidome of PBMC and on the Lateral Diffusion of ß<sub>1</sub>-Adrenergic Receptors in C6 Cells

Stress causes pathological changes in the signal transduction of neurotransmitter systems, which can lead to depression. Signaling relies not only on receptor-ligand interactions and subsequent regulatory processes, but also on the composition of the surrounding lipid bilayer, which has a decisive influence on the behavior of receptors. 
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\nThe aim of the present study was to investigate the influence of the St. John’s wort extract Ze117 on the lipid composition of cortisol-stressed peripheral blood mononuclear cells (PBMC) and on the lateral mobility of β<sub>1</sub>-adrenergic receptors (β<sub>1</sub>AR) in C6 cells. 
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\nThe influence of Ze117 on the membrane fluidity of PBMC compared to cortisol was investigated by fluorescence anisotropy measurements. Changes in phospholipids in terms of the average number of double bounds and the average chain lengths under the influence of cortisol compared to untreated control cells were analyzed by mass spectrometry. Compared to cortisol treated cells, simultaneous incubation of cells with cortisol and Ze177 was investigated. 
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\nInfluence of Ze117 on lateral mobility of SNAP-tagged β<sub>1</sub>AR in the plasma membrane of C6 cells was analysed under both non-stimulating and isoprenaline-stimulating conditions. Single particle tracking (SPT) was used to observe the lateral diffusion of β<sub>1</sub>AR, whereby the registered trajectories were evaluated by variational Bayesian treatment of a hidden Markov model (vbSPT) and packing coefficient (Pc) analysis with respect to diffusion coefficients, receptor state occupancies and confinement. 
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\nThe results of this work show that Ze117 has a decreasing effect on membrane fluidity in PBMC compared to an increased membrane fluidity after cortisol preincubation. An increased average number of double bonds and carbon atoms in fatty acids of certain phospholipid classes in cortisol pretreated cells were reversed by Ze117. 
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\nThe membrane fluidity essentially depends on the phospholipid composition. Ze117 therefore normalizes the membrane fluidity of cortisol-stressed cells. In particular, the decrease in the number of double bonds in fatty acids under Ze117 suggests an increase in membrane rigidity, which counteracts the cortisol effect. 
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\nMost likely, the membrane composition also has effects on receptor systems as demonstrated by findings of SPT experiments. In C6 cells overexpressing SNAP-tagged β<sub>1</sub>AR (SNAP-β<sub>1</sub>AR) three individual diffusive states for SNAP-β<sub>1</sub>AR were detected. Each state was defined by a diffusion coefficient, a corresponding state occupancy value and the confinement area. The states were classified as an immobile state S1, a slow diffusing state S2, and a fast diffusing state S3. 
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\nAfter stimulation of control cells with isoprenaline, the fraction of the immobile state S1 was more pronounced compared to unstimulated cells, whereas confinement of SNAP-β<sub>1</sub>AR was not affected. After preincubation with Ze117 the diffusion coefficients of S1 and S2 decreased compared to control cells, indicating a hindered diffusion. Additionally, the fraction of the immobile diffusive state S1 increased and the confinement area decreased, indicating regulatory responses of the cell and altered receptor environment. 
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\nThe findings of this work might contribute to new insights on the pathogenesis and treatment of depression and on a new mode of action of the herbal antidepressant St. John’s wort.

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