Office Phone: 318-675-7855
Laboratory Phone: 318-675-7865
Office Fax: 318-675-5180
B.S., 1981, Longwood College
Ph.D., 1989, Kent State University
Dr. Leidenheimer's major research interests focus on the function, trafficking and degradation of GABAA receptors, with particular emphasis on their regulation by protein phosphorylation.
GABAA receptors are the major inhibitory neurotransmitter receptors in the central nervous system. The GABAA receptor is a heteropentameric ligand-gated chloride channel that is activated by the neurotransmitter g-aminobutyric acid (GABA). Once activated, chloride influx through the central ion channel results in membrane hyperpolarization. Abnormalities in receptor function are linked to the pathogenesis of a variety of neurological and psychiatric disorders including epilepsy, insomnia and anxiety. The GABAA receptor is the site of action of several classes of widely-used therapeutic agents such as benzodiazepines, barbiturates and anesthetics.
To participate in neurotransmission, the GABAA receptor must reside on the cell surface. The trafficking of the receptor to and from the cell surface is, therefore, a major determinant of the efficacy of GABAergic neurotransmission. The lab has a long-standing interest in GABAA receptor trafficking. Most recently, we have demonstrated that GABA itself can act as a ligand chaperone in the endoplasmic reticulum (ER) to facilitate the biogenesis, and subsequently the surface expression, of recombinant GABAa receptors (Eshaq et al., 2010). This is the first direct demonstration that a neurotransmitter can act as a ligand chaperone for its receptor. We now have strong evidence that this phenomenon also occurs in neuronal cultures. The neurotransmitter as ligand chaperone hypothesis raises many intriguing questions such as: What is the physiological significance of such chaperoning? Does the ER contain a reservoir of receptor intermediates from which receptor can be rapidly assembled in response to changing levels of the cognate ligand? How do neurotransmitters access the ER lumen? What are the molecular mechanisms by which GABA binding promotes GABAA receptor biogenesis? Can therapeutically useful ligand chaperones (i.e., pharmacological chaperones) that target GABAa receptors be developed?
Experimental systems in use include both primary neuronal cultures and HEK 293 cells expressing recombinant wild type and mutant GABAA receptors. Confocal microscopy and flow cytometry are used to visualize/quantify trafficking of receptors labeled either immunologically or with fluorescent protein tags. Complementary biochemical techniques, including receptor cell surface biotinylation assays, glycosidase digests and immunoprecipitation, are employed to assess mechanisms of receptor biogenesis and trafficking.
All Publications: PubMed