0 avis
Depletion of membrane cholesterol modifies structure, dynamic and activation of Nav1.7
Archive ouverte
International audience. Cholesterol is a major component of plasma membranes and unsurprisingly plays a significant role in actively regulating the functioning of several membrane proteins in humans. Notably, recent studies have shown that cholesterol depletion can also impact transmission of potentially painful signals in the context of peripheral inflammation, via hyperexcitability of the voltage-gated sodium channel (Nav) subtype 1.9, but the structural mechanisms underlying this regulation remain to be elucidated. In this study, we focus on the role of cholesterol depletion on Nav1.7, which is primarily expressed in the peripheral sensory neurons and linked to various chronic inherited pain syndromes. Coarse-grained molecular dynamics simulations shed light on the dynamic changes of the geometry of Nav1.7 upon membrane cholesterol depletion: A loss of rigidity at key structural motifs linked to activation and fast-inactivation is observed, as well as changes in the geometry of drug-binding regions in the channel. Loss of rigidity in cholesterol depleted conditions should allow the channel to transition between different gating states more easily. In-vitro whole-cell patch clamp experiments on HEK293t cells expressing Nav1.7 validated these predictions made in silico at the functional level. Hyperpolarizing shifts in the voltage-dependence of activation and fast-inactivation were observed along with an acceleration of the time to peak and onset kinetics of fast inactivation. These results underline the critical role of membrane composition, and of cholesterol in particular, in influencing Nav1.7 gating characteristics. Furthermore, our results hint to a key role of the membrane environment in affecting drug effects and in pathophysiological dysregulation, sharpening our approaches for analgesics design.
Consulter en ligne
Suggestions
Du même auteur
