Phosphatidylinositol 4,5-bisphosphate (PIP₂) facilitates norepinephrine transporter dimerization and modulates substrate efflux.

ABSTRACT: The plasmalemmal norepinephrine transporter (NET) regulates cardiovascular sympathetic activity by clearing extracellular norepinephrine in the synaptic cleft. Here, we investigate the subunit stoichiometry and function of NET using single-molecule fluorescence microscopy and flux assays. In particular, we show the effect of phosphatidylinositol 4,5-bisphosphate (PIP₂) on NET oligomerization and efflux. NET forms monomers (~60%) and dimers (~40%) at the plasma membrane. PIP₂ depletion results in a decrease in the average oligomeric state and decreases NET-mediated substrate efflux while not affecting substrate uptake. Mutation of the putative PIP₂ binding residues R121, K334, and R440 to alanines does not affect NET dimerization but results in decreased sub

SUBMITTER: Luethi D 

PROVIDER: S-EPMC9672106 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature