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.