title: Calcium regulation in mouse mesencephalic neurons-Differential roles of Na(+)/Ca(2+) exchanger, mitochondria and endoplasmic reticulum.
abstract: Midbrain dopaminergic (DA) neurons are the key to finely tune the voluntary movement, habit and motivation. The progressive and selective degeneration of these neurons is a pathological hallmark of Parkinson's disease (PD). The susceptibility of DA neurons in the SNpc may result from differences in how Ca(2+) is handled. However, very little information is available about the mechanisms involved in the regulation of intracellular Ca(2+) concentration ([Ca(2+)]i) in DA neurons. In this study, the relative contributions of various Na(+)/Ca(2+) exchangers and their interplay with internal Ca(2+) stores, endoplasmic reticulum (ER) and the mitochondria, in the regulation of the [Ca(2+)]i of mouse mesencephalic neurons were characterized. Both the K(+)-dependent Na(+)/Ca(2+) exchanger (NCKX) and the K(+)-independent Na(+)/Ca(2+) exchanger (NCX) can be detected and are functional in DA and non-DA neurons. NCX accounts for the larger component of Na(+)/Ca(2+) exchange activity. Single-cell RT-PCR analysis showed each individual neuron expressed a distinct set of the Na(+)/Ca(2+) exchangers. Furthermore, the Na(+)/Ca(2+) exchangers play prominent roles in removing [Ca(2+)]i induced by glutamate but not [Ca(2+)]i induced by depolarization. The mitochondria serve as a major Ca(2+) sink and are functionally located close to NCX. In contrast, the ER is functionally located close to NCKX and acts primarily as a Ca(2+) source with marginal effects. This study reveals that the Na(+)/Ca(2+) exchangers, the ER and the mitochondria, which cooperate interactively, act similarly when regulating [Ca(2+)]i in mesencephalic DA and non-DA neurons. The heterogeneous expression of multiple types of Na(+)/Ca(2+) exchangers and the quantitative differences found in [Ca(2+)]i regulation, together with other risk factors specific to DA neurons such as dopamine oxidation resulting in oxidative stress, may drive these cells to undergo selective degeneration.
authors.affiliation: Brain Research Center, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Wu
authors.affiliation: Brain Research Center, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan, ROC. Electronic address: lskao@ym.edu.tw.
authors.forename: Lung-Sen
authors.initials: LS
authors.lastname: Kao
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005971:Glutamates / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D008636:Mesencephalon / Q000166:cytology*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D005971:Glutamates; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; C074530:potassium-dependent sodium-calcium exchanger; D011188:Potassium; D002118:Calcium
keywords: Ca(2+); Dopaminergic neurons; Endoplasmic reticulum; Mitochondria; Na(+)/Ca(2+) exchanger; Parkinson’s disease