Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Luethi, D; Maier, J; Rudin, D; Szöllősi, D; Angenoorth, TJF; Stankovic, S; Schittmayer, M; Burger, I; Yang, JW; Jaentsch, K; Holy, M; Das, AK; Brameshuber, M; Camacho-Hernandez, GA; Casiraghi, A; Newman, AH; Kudlacek, O; Birner-Gruenberger, R; Stockner, T; Schütz, GJ; Sitte, HH.
Phosphatidylinositol 4,5-bisphosphate (PIP2) facilitates norepinephrine transporter dimerization and modulates substrate efflux.
Commun Biol. 2022; 5(1):1259
Doi: 10.1038/s42003-022-04210-1
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- Co-Autor*innen der Med Uni Graz
- Birner-Grünberger Ruth
- Schittmayer-Schantl Matthias
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- 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 substrate efflux that is not altered upon PIP2 depletion; this indicates that PIP2 interactions with these residues affect NET-mediated efflux. A dysregulation of norepinephrine and PIP2 signaling have both been implicated in neuropsychiatric and cardiovascular diseases. This study provides evidence that PIP2 directly regulates NET organization and function.
- Find related publications in this database (using NLM MeSH Indexing)
- Norepinephrine Plasma Membrane Transport Proteins - genetics
- Phosphatidylinositols - administration & dosage
- Dimerization - administration & dosage
- Biological Transport - administration & dosage
- Inositol Phosphates - administration & dosage
- Norepinephrine - administration & dosage