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.

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Sigma-1 receptors (σ-1Rs) are chaperone-like proteins that are broadly distributed throughout the central nervous system and in other tissues. They have been implicated in several physiological and pathological processes, primarily by their ability to modulate certain voltage- and ligand-gated ion channels. Growing evidence suggests that σ-1Rs regulate the functions of ion channels, such as voltage-gated K+ 1.2 (Kv 1.2) and the human Ether-à-go-go-Related Gene (hERG) ion channels, by modulating their expression, trafficking, and targeting. While it is well documented that σ-1Rs enhance the function of N-methyl-D-aspartate receptors (NMDARs), the mechanisms of this enhancement remain poorly understood. Using biochemical methods, we show that 90 minutes after intraperitoneal (i.p.) injection of σ-1R agonists such as (+)-SKF 10,047 (SKF) or (+)-Pentazocine (PTZ) (2 mg/kg), there is an increase in the expression of GluN2 subunits of NMDARs and postsynaptic density protein-95 (PSD-95) in the rat hippocampus. Following activation of σ-1Rs, co-immunoprecipitation (Co-IP) experiments reveal an increased interaction between σ-1Rs and NMDAR subunits; sucrose gradient centrifugation demonstrates an increase in the protein levels of GluN2 subunits in vesicular compartment; and biotinylation shows an increase in the surface levels of GluN2A-containing NMDARs. Taken together, our results suggest σ-1Rs may enhance NMDARs function by increasing their expression, trafficking, and surface levels. This σ-1R-mediated increase in NMDAR expression and surface levels might be involved in several physiological processes such as learning and memory. Our findings also suggest that σ-1Rs could form a potential target for designing novel antipsychotics.

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves [110]-127).

Thesis (Ph.D.)--Biology, Georgia Institute of Technology, 2008. / Committee Chair: Dr. Nael A. McCarty; Committee Co-Chair: Dr. Darrell Jackson; Committee Member: Dr. Alfred H. Merrill; Committee Member: Dr. Barbara D. Boyan; Committee Member: Dr. Harish Radhakrishna; Committee Member: Dr. Marion B. Sewer

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2005. / Includes bibliographical references (leaves 136-146). Also available in electronic version.

A novel solubilising agent (0.l% sodium cholate-lM NaCl) has been developed which will solubilise 10-30% of muscarinic cholinergic receptors from bovine caudate nucleus. Using the muscarinic antagonist quinuclidinyl benzilate (QNB), a single saturable binding component was found with an equilibrium constant of ZOOpM, approximately 10-fold higher than the membrane receptor and 4-fold higher than the ratio k_-l/k_l determined kinetically in the soluble material. This latter difference may indicate that the binding of QNB to the solubilised receptor is not a simple second-order process. Inhibition constants for a variety of muscarinic agonists and antagonists were 10 to 20-fold higher than in the membrane state and non-muscarinic ligands were without effect. The decrease in affinity was shown to be due to the presence of high salt. Evidence was presented that the apparent increase in Hill coefficient for muscarinic agonist binding to soluble material was not due to a differential solubilisation of muscarinic receptors or to a conformational change of high to low affinity agonist sites during the solubilisation. Instead the Hill coefficient of the soluble material decreased as the percentage of total binding sites solubilised increased. The stability of receptor binding at different temperatures was shown to be dependent on the protein: cholate (w/w) ratio. Results from gel filtration, affinity chromotography and immunization studies are also reported. The results of this thesis are discussed in the light of the possible importance of phospholipids for receptor activity.

The sigma-1 receptors (σ-1Rs) are endoplasmic reticulum (ER) resident proteins shown to have chaperone-like functions, and are widely distributed throughout the central nervous system (CNS). They reside at a specialized membrane called mitochondria- associated ER-membrane (MAM) and can modulate numerous voltage- and ligand-gated ion channels. One of these channels is the N-methyl-D-aspartate receptor (NMDAR), and σ-1R ligands are able to enhance the potentiation of NMDARs, but the mechanism involved remains poorly understood. Using various biochemical techniques, we show that 90 min following an i.p. injection of σ-1R agonists ((+)-SKF 10,047 (SKF), (+)- Pentazocine (PTZ), or PRE-084 (PRE), there is an increase in the expression of GluN2- containing NMDARs in the rat hippocampus. These results suggest that σ-1R activation is able to enhance NMDAR function by modulating protein expression levels both in the cytosol and on the cell surface. This suggests that σ-1Rs could be excellent therapeutic targets for many neurological disorders, and for the development of novel antipsychotics.