Structural and mechanistic studies of ligand-gated neurotransmitter receptors
Abstract
Structural and Mechanistic Studies of Ligand-Gated Neurotransmitter Receptors The present dissertation focuses on the structure and function of two specific types of ligand-gated neurotransmitter receptors, namely the glutamate and γ-aminobutyric acidA (GABAA ) receptors. This investigation is of significant importance since the dysfunction of these receptors is implicated in various neurological diseases and trauma ranging from panic disorder to epilepsy. The present investigation addresses how structural differences between the agonists and antagonists binding to the AMPA-type glutamate receptor were elucidated by Fourier Transform Infrared spectroscopy. Such an investigation of the structural differences in the receptor, upon binding to these ligands, provides insight into the differences in the strength and nature of inter- and intea-molecular interactions (i.e. hydrogen and electrostatic interactions) between ligand and protein. In addition, it also addresses how specific alterations in receptors for the inhibitory neurotransmitter, GABAA influence the induction and propagation of epileptic seizures. The underlying function and mRNA expression levels of the GABAA receptors in a genetically epileptic prone rat, termed GEPR-3, was elucidated using electrophysiology and In situ hybridization techniques. From these investigations specific alterations were detected in the steps that lead to the opening GABAA receptor channel, upon binding GABA, in the GEPR-3 rats relative to normal rats. Moreover, the mRNA expression of the β1 subunit of GABAA receptor was significantly down regulated in GEPR-3 rats relative to normal rats. The modulatory action of an anticonvulsant drug, diazepam, on the function of the GABAA receptor in normal rats was also investigated. The modulatory action of diazepam on hippocampal neurons was found to be predominantly through an increase in channel conductance of the GABAA receptor unlike that seen for spinal cord neurons. The differences in the mechanisms of action of diazepam between spinal cord neurons and hippocampal neurons on the GABAA receptor mediated currents may be attributed to the existence of the different GABAA receptor subtypes.
This paper has been withdrawn.