Dr. N.J. Leidenheimer’s Research Focus

Research interests

MGABAA receptors are the major inhibitory neurotransmitter receptors in the central nervous system. Abnormalities in receptor function are linked to the pathogenesis of a variety of psychiatric and neurological disorders. In addition to its role in disease processes, the receptor is the site of action of therapeutically important drugs such as the benzodiazepines, barbiturates and several anesthetics. The GABAA receptor is a pentameric ligand-gated chloride channel that is activated by the neurotransmitter g–aminobutyric acid. To participate in synaptic transmission the receptor must be localized on the cell surface at the neuronal synapse. Our laboratory examines the mechanisms by which GABAA receptors are trafficked to and from the cell surface. We have recently found that the GABAA receptor undergoes dynamin-mediated endocytosis that involves a dileucine AP2 recognition motif on the b subunit of the receptor. This endocytosis is accelerated by PKC-dependent phosphorylation, the molecular mechanisms of which are being investigated. We are also currently examining post endocytic receptor trafficking including Rab11 dependent recycling of the receptor and lysosomal degradation. Additionally, we are investigating the significance of a transplantable nuclear localization signal that we have recently identified on the receptor gamma subunit. For our experimental systems we use both primary neuronal cultures and recombinant wildtype and mutant GABAA receptors expressed in HEK 293 cells. Confocal microscopy is used to visualize receptor immunofluorescence and GFP tagged receptor constructs. Cell surface biotinylation assays/Western blotting are employed to assess receptor cell surface levels and the electrophysiological technique of patch-clamp is used to measure ion channel function.