{"id":{"repo_id":"wichita-thes","oai_identifier":"oai:soar.wichita.edu:10057/11600"},"canonical_url":"https://search.dev.ndltd.org/etd/wichita-thes/oai:soar.wichita.edu:10057/11600","repository":{"repo_id":"wichita-thes","name":"Wichita State University","base_url":"https://soar.wichita.edu/oai/request"},"display":{"title":"Part I: Extracellular hydrogen ions activate tyrosine hydroxylase in catecholaminergic cells Part II: Identification of novel mechanism(s) of Parkinson's disease causing 1-methyl-4-phenylpyridinium neurotoxicity","abstract":"Tyrosine hydroxylase (TH) is the rate-limiting step of the catecholamine biosynthetic pathway, thus, in theory, modulating the TH activity could be a target for therapeutic purposes. Despite extensive studies, there are significant deficiencies in the current model of in vivo TH activation. In the present study, we report the discovery that the [H+]o stimulate the TH activity in MN9D and PC12 cells under physiologically attainable concentrations. The [H+]o-dependent activation of TH requires [Cl-]o, but not Na+ or Ca2+. In addition, while the Cl-/HCO3- transporter inhibitor, 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid, inhibits TH activation, the Na+/H+ exchanger inhibitor, amiloride, potentiates it. [H+]o increases the [H+]i , [Ca2+]i and phosphorylation of Ser 40, the regulatory domain of TH. Based on these and other findings, we propose that the increase of [H+]o and/or intracellular alkalinity during the exocytotic release of acidic content from the synaptic vesicles may signal in vivo TH activation. Part II of my research is focused on Parkinson's disease causing N-methyl-4-phenylpyridinium (MPP+). Although selective dopaminergic toxicity of MPP+ is due to the specific uptake through the dopamine transporter (DAT), recent studies show that MPP+ is taken through multiple pathways in dopaminergic cells and other cells. Here we show that a previously unidentified Na+/Cl--independent, Ca2+-sensitive MPP+ uptake pathway is present specifically in dopaminergic cells but not in other cell types. We further show that the toxicity of MPP+ may be associated with the unidentified Na+/Cl--independent, Ca2+-sensitive MPP+ uptake pathway. Therefore, we propose that the specific dopaminergic toxicity of MPP+ could be a consequence of its interference with the physiological function(s) of this transporter and a better understanding of its physiological role may provide clues to the etiology of sporadic PD.","abstract_html":"Tyrosine hydroxylase (TH) is the rate-limiting step of the catecholamine biosynthetic pathway, thus, in theory, modulating the TH activity could be a target for therapeutic purposes. Despite extensive studies, there are significant deficiencies in the current model of in vivo TH activation. In the present study, we report the discovery that the [H+]o stimulate the TH activity in MN9D and PC12 cells under physiologically attainable concentrations. The [H+]o-dependent activation of TH requires [Cl-]o, but not Na+ or Ca2+. In addition, while the Cl-/HCO3- transporter inhibitor, 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid, inhibits TH activation, the Na+/H+ exchanger inhibitor, amiloride, potentiates it. [H+]o increases the [H+]i , [Ca2+]i and phosphorylation of Ser 40, the regulatory domain of TH. Based on these and other findings, we propose that the increase of [H+]o and/or intracellular alkalinity during the exocytotic release of acidic content from the synaptic vesicles may signal in vivo TH activation. Part II of my research is focused on Parkinson's disease causing N-methyl-4-phenylpyridinium (MPP+). Although selective dopaminergic toxicity of MPP+ is due to the specific uptake through the dopamine transporter (DAT), recent studies show that MPP+ is taken through multiple pathways in dopaminergic cells and other cells. Here we show that a previously unidentified Na+/Cl--independent, Ca2+-sensitive MPP+ uptake pathway is present specifically in dopaminergic cells but not in other cell types. We further show that the toxicity of MPP+ may be associated with the unidentified Na+/Cl--independent, Ca2+-sensitive MPP+ uptake pathway. Therefore, we propose that the specific dopaminergic toxicity of MPP+ could be a consequence of its interference with the physiological function(s) of this transporter and a better understanding of its physiological role may provide clues to the etiology of sporadic PD.","abstract_has_math":false,"creators":["Le, Viet Q."],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-05","date_published":"2015-05","updated_at":"2026-07-24T06:06:23Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["hdl:10057/11600"],"render_values":[{"text":"hdl:10057/11600","href":null,"code":true}]}]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2015-05"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["hdl:10057/11600"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.other","label":"Dc Description Other","values":["Tyrosine hydroxylase (TH) is the rate-limiting step of the catecholamine biosynthetic pathway, thus, in theory, modulating the TH activity could be a target for therapeutic purposes. Despite extensive studies, there are significant deficiencies in the current model of in vivo TH activation. In the present study, we report the discovery that the [H+]o stimulate the TH activity in MN9D and PC12 cells under physiologically attainable concentrations. The [H+]o-dependent activation of TH requires [Cl-]o, but not Na+ or Ca2+. In addition, while the Cl-/HCO3- transporter inhibitor, 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid, inhibits TH activation, the Na+/H+ exchanger inhibitor, amiloride, potentiates it. [H+]o increases the [H+]i , [Ca2+]i and phosphorylation of Ser 40, the regulatory domain of TH. Based on these and other findings, we propose that the increase of [H+]o and/or intracellular alkalinity during the exocytotic release of acidic content from the synaptic vesicles may signal in vivo TH activation. Part II of my research is focused on Parkinson's disease causing N-methyl-4-phenylpyridinium (MPP+). Although selective dopaminergic toxicity of MPP+ is due to the specific uptake through the dopamine transporter (DAT), recent studies show that MPP+ is taken through multiple pathways in dopaminergic cells and other cells. Here we show that a previously unidentified Na+/Cl--independent, Ca2+-sensitive MPP+ uptake pathway is present specifically in dopaminergic cells but not in other cell types. We further show that the toxicity of MPP+ may be associated with the unidentified Na+/Cl--independent, Ca2+-sensitive MPP+ uptake pathway. Therefore, we propose that the specific dopaminergic toxicity of MPP+ could be a consequence of its interference with the physiological function(s) of this transporter and a better understanding of its physiological role may provide clues to the etiology of sporadic PD."]},{"key":"dc:title","label":"Title","values":["Part I: Extracellular hydrogen ions activate tyrosine hydroxylase in catecholaminergic cells Part II: Identification of novel mechanism(s) of Parkinson's disease causing 1-methyl-4-phenylpyridinium neurotoxicity"]}]}],"canonical_facts":{"dc:date.issued":["2015-05"],"dc:description.other":["Tyrosine hydroxylase (TH) is the rate-limiting step of the catecholamine biosynthetic pathway, thus, in theory, modulating the TH activity could be a target for therapeutic purposes. Despite extensive studies, there are significant deficiencies in the current model of in vivo TH activation. In the present study, we report the discovery that the [H+]o stimulate the TH activity in MN9D and PC12 cells under physiologically attainable concentrations. The [H+]o-dependent activation of TH requires [Cl-]o, but not Na+ or Ca2+. In addition, while the Cl-/HCO3- transporter inhibitor, 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid, inhibits TH activation, the Na+/H+ exchanger inhibitor, amiloride, potentiates it. [H+]o increases the [H+]i , [Ca2+]i and phosphorylation of Ser 40, the regulatory domain of TH. Based on these and other findings, we propose that the increase of [H+]o and/or intracellular alkalinity during the exocytotic release of acidic content from the synaptic vesicles may signal in vivo TH activation. Part II of my research is focused on Parkinson's disease causing N-methyl-4-phenylpyridinium (MPP+). Although selective dopaminergic toxicity of MPP+ is due to the specific uptake through the dopamine transporter (DAT), recent studies show that MPP+ is taken through multiple pathways in dopaminergic cells and other cells. Here we show that a previously unidentified Na+/Cl--independent, Ca2+-sensitive MPP+ uptake pathway is present specifically in dopaminergic cells but not in other cell types. We further show that the toxicity of MPP+ may be associated with the unidentified Na+/Cl--independent, Ca2+-sensitive MPP+ uptake pathway. Therefore, we propose that the specific dopaminergic toxicity of MPP+ could be a consequence of its interference with the physiological function(s) of this transporter and a better understanding of its physiological role may provide clues to the etiology of sporadic PD."],"dc:identifier":["hdl:10057/11600"],"dc:title":["Part I: Extracellular hydrogen ions activate tyrosine hydroxylase in catecholaminergic cells Part II: Identification of novel mechanism(s) of Parkinson's disease causing 1-methyl-4-phenylpyridinium neurotoxicity"],"dc:type":["Dissertation"]},"updated_at":"2026-07-24T06:06:23Z"}