The main aim of this project was to determine the neurotrophic actions of glial cell line-derived neurotrophic factor (GDNF) and neurturin, two novel members of the transforming growth factor-beta superfamily of proteins, on neurons from the peripheral nervous system and to identify their receptors. It is found that GDNF promotes the survival of multiple populations of chicken sensory and autonomic neurons in culture throughout development. Whereas sympathetic, parasympathetic and propioceptive neurons become less responsive to GDNF with age, enteroceptive and sensory cutaneous neurons become more responsive to GDNF. GDNF mRNA is expressed in the tissues innervated by these neurons, and developmental changes in its expression in several tissues mirror the changing responses of the innervating neurons to GDNF. These results have changed the previous notion that GDNF is a highly specific neurotrophic factor for motoneurons and dopaminergic neurons. It is shown that neurturin, which is structurally related to GDNF, also promotes the in vitro survival of embryonic chicken sensory and autonomic neurons. Thus, GDNF and neurturin compose a novel subfamily of homologous neurotrophic factors with a similar pattern of activity. The cloning of chicken GDNF receptor-α (GDNFR-α) and a novel receptor termed neurturin receptor-α (NTNR-α) is reported. GDNFR-α and NTNR-α are homologous receptors linked to the membrane via a glycosyl- phosphatidylinositol linkage. It is shown that ectopic co-expression in neurons of GDNFR-α with RET (rearranged during transfection), a transmembrane receptor tyrosine kinase, confers a survival response to GDNF, but not neurturin, and that co-expression of NTNR-α with RET confers a survival response to neurturin, but not GDNF. GDNFR-α and NTNR-α mRNAs are widely expressed in the nervous system, including GDNF and neurturin responsive neurons, and in non-neuronal tissues. These findings indicate that GDNF and neurturin promote neuronal survival by signalling via similar multicomponent receptors that consist of a common transducing receptor tyrosine kinase and a member of a newly emerging family of glycosyl-phosphatidylinositol-linked receptors that confer ligand- specificity.

No description available.

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2006. / Includes bibliographical references (leaves 215-232). Also available in electronic version.

Thesis (Ph. D.)--University of Sydney, 2003. / Title from title screen (viewed Apr. 28, 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Dept. of Medicine, Nepean Hospital, Faculty of Medicine. Includes bibliography. Also available in print form.

Thesis (Ph. D.)--University of Texas at Austin, 2008. / Title from PDF title page (University of Texas Digital Repository, viewed on September 9, 2009). Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 2005. / Vita. Includes bibliographical references.

In the present study non-5-HT₁(A)/non-5-HT₁(C) binding sites in the rabbit caudate nucleus (CN) were examined to determine if they might be identical to the recently discovered 5-HT₁(D) sites in the bovine CN. The characterizations were carried out measuring high-affinity [³H]5-HT binding under conditions where 5-HT₁(A) and 5-HT₁(C) sites were pharmacologically masked in both tissues. Comparison of the pharmacologic profiles of the bovine 5-HT₁(D) and rabbit non-5-HT₁(A)/non-5-HT₁(C) sites revealed similarities, but showed distinct differences. [³H]5-HT binding in the bovine CN was significantly more sensitive to inhibition by GTP than was [³H]5-HT binding in the rabbit CN, and this effect was differentially sensitive to calcium and other divalent cations (i.e., Mg²⁺, Mn²+)⁺in the two tissues. [³H]5-HT binding in the bovine CN was significantly more sensitive to inhibition by NEM than it was in the rabbit CN. Thus, it may be concluded that the non-5-HT₁(A)/non-5-HT₁(C) [³H]5-HT binding sites in rabbit CN are distinct from those in the bovine CN, and we propose that they be tentatively identified as 5-HT₁(R) to distinguish them from the 5-HT₁(D) site.

Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2003. / Includes bibliographical references (leaves 127-140). Also available in electronic version. Access restricted to campus users.

The glycine receptor (GlyR) is the major inhibitory ligand-gated ion channel in the brainstem and spinal cord. It is a member of the Cys-loop superfamily of ligand-gated ion channels that includes serotonin-3, GABA[subscript A] and nicotinic acetylcholine (nAChR) receptors. Individual subunits are comprised of a large extracellular N-terminal agonist binding domain, four transmembrane (TM) segments and a large cytoplasmic loop between TM3 and TM4, containing phosphorylation sites (Brejc et al. 2001, Unwin, 2005). These receptors are pentameric in structure, with the TM2 region of each subunit contributing to the formation of a central ion pore (Lynch 2004). While the TM2-3 linker region has been hypothesized to be important for signal transduction thoughout the Cys-loop family, the precise structure and function of this region is unclear. We hypothesized that the TM2-3 linker region is a point of connection between subunits. We used disulfide bond trapping to show that the TM2-3 is able to interact with adjacent subunits and plays a critical role in signal transduction. In addition, we provide experimental evidence that the structure of the TM2-3 linker region in the [alpha]1 GlyR is a [beta]-sheet. We next sought to determine the role of the TM2-3 linker region in allosteric modulation. Using two-electrode voltage clamp electrophysiology we found that the TM2-3 linker can determine the direction of modulation without affecting modulator binding. Finally, we wanted to determine if a single alcohol and anesthetic binding site could be occupied to prevent EtOH molecules from binding. Using a combination of thiol reagents and disulfide bond trapping we show that a residue previously identified as important for the binding of alcohols and anesthetics interacts within the pore. We were unable to increase the volume at residue-267 such that EtOH was unable to bind, suggesting that EtOH may have more than one binding pocket. Together, these findings suggest that the TM2-3 linker plays a critical role in signal transduction and receptor modulation providing a foundation for future work on this region in the GlyR. / text

Thesis (Ph. D.)--University of Adelaide, Dept. of Physiology, 1984. / Includes bibliographical references (leaves 118-161).