Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function

A wide variety of phytochemicals are consumed for their perceived health benefits. Many of these phytochemicals have been found to alter numerous cell functions, but the mechanisms underlying their biological activity tend to be poorly understood. Phenolic phytochemicals are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examined five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochemicals alters lipid bilayer properties and the function of diverse membrane proteins. Molecular dynamics simulations show that these phytochemicals modify bilayer properties by localizing to the bilayer/solution interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochemicals, consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochemicals are due to cell membrane perturbations, rather than specific protein binding

A model for the recovery kinetics of rod phototransduction, based on the enzymatic deactivation of rhodopsin.

We propose a model for the recovery of the retinal rod photoresponse after a short stimulus. The approach describes the enzymatic deactivation of the photoactivated receptor, rhodopsin, by simple enzyme kinetics. An important feature of this description is that the R* deactivation obeys different time laws, depending on the numbers of R* formed per disc membrane and available enzyme molecules. If the enzyme works below substrate saturation, the rate of deactivation depends linearly on the number of R*, whereas for substrate saturation a hyperbolic relation--the well-known Michaelis-Menten equation--applies. This dichotomy is used to explain experimental finding that the relation between the saturation time of the photoresponse after short illumination and the flash strength has two sharply separated branches for low and high flash intensities (up to approximately 10% bleaching). By relating both branches to properties of the enzymatic rhodopsin deactivation, the new model transcends the classical notion of a constant characteristic lifetime of activated rhodopsin. With parameters that are plausible in the light of the available data and the additional information that the deactivating enzyme, rhodopsin kinase, and the signaling G-protein, transducin, compete for the active receptor, the slopes of the saturation function are correctly reproduced

Dynamical study of Na v channel excitability under mechanical stress

Alteration of Na v channel functions (channe-lopathies) has been encountered in various hereditary muscle diseases. Na v channel mutations lead to aberrant excitabil-ity in skeletal muscle myotonia and paralysis. In general, these mutations disable inactivation of the Na v channel, producing either repetitive action potential firing (myotonia) or electrical dormancy (flaccid paralysis) in skeletal muscles. These " sick-excitable " cell conditions were shown to correlate with a mechanical stretch-driven left shift of the conductance factors of the two gating mechanisms of a fraction of Na v channels, which make them firing at inappropriate hyperpolarised (left-shifted) voltages. Here we elaborate on a variant of the Hodgkin–Huxley model that includes a stretch elasticity energy component in the activation and inactivation gate kinetic rates. We show that this model reproduces fairly well sick-excitable cell behaviour and can be used to predict the parameter domains where aberrant excitability or paralysis may occur. By allowing us to separate the incidences of activation and inactivation gate impairments in Na v channel excitability, this model could be a strong asset for diagnosing the origin of excitable cell disorders