The Antidiabetic Drug Metformin Regulates Voltage-Gated Sodium Channel Na_V1.7 via the Ubiquitin-Ligase NEDD4-2.

ABSTRACT: The antidiabetic drug metformin has been shown to reduce pain hypersensitivity in preclinical models of chronic pain and in neuropathic pain in humans. Multiple intracellular pathways have been described as metformin targets. Among them, metformin is an activator of the adenosine 5'-monophosphate protein kinase that can in turn modulate the activity of the E3 ubiquitin ligase NEDD4-2 and thus post-translational expression of voltage-gated sodium channels (Na_Vs). In this study, we found that the bulk of the effect of metformin on Na1.7 is dependent on NEDD4-2. In HEK cells, the expression of Na_V1.7 at the membrane fraction, obtained by a biotinylation approach, is only reduced by metformin when cotransfected with NEDD4-2. Similarly, in voltage-clamp recordings, metform

SUBMITTER: Deftu AF 

PROVIDER: S-EPMC8906783 | biostudies-literature | 2022 Mar-Apr

REPOSITORIES: biostudies-literature