Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson's.

Autor: Brimblecombe KR; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, Maryland, USA., Connor-Robson N; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK., Bataille CJR; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK.; Department of Pharmacology, University of Oxford, Oxford, UK., Roberts BM; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK., Gracie C; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK., O'Connor B; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK., Te Water Naude R; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK., Karthik G; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK., Russell AJ; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK.; Department of Pharmacology, University of Oxford, Oxford, UK., Wade-Martins R; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, Maryland, USA., Cragg SJ; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, Maryland, USA.
Jazyk: angličtina
Zdroj: The European journal of neuroscience [Eur J Neurosci] 2024 Mar; Vol. 59 (6), pp. 1242-1259. Date of Electronic Publication: 2023 Nov 08.
DOI: 10.1111/ejn.16180
Abstrakt: Ca 2+ entry into nigrostriatal dopamine (DA) neurons and axons via L-type voltage-gated Ca 2+ channels (LTCCs) contributes, respectively, to pacemaker activity and DA release and has long been thought to contribute to vulnerability to degeneration in Parkinson's disease. LTCC function is greater in DA axons and neurons from substantia nigra pars compacta than from ventral tegmental area, but this is not explained by channel expression level. We tested the hypothesis that LTCC control of DA release is governed rather by local mechanisms, focussing on candidate biological factors known to operate differently between types of DA neurons and/or be associated with their differing vulnerability to parkinsonism, including biological sex, α-synuclein, DA transporters (DATs) and calbindin-D28k (Calb1). We detected evoked DA release ex vivo in mouse striatal slices using fast-scan cyclic voltammetry and assessed LTCC support of DA release by detecting the inhibition of DA release by the LTCC inhibitors isradipine or CP8. Using genetic knockouts or pharmacological manipulations, we identified that striatal LTCC support of DA release depended on multiple intersecting factors, in a regionally and sexually divergent manner. LTCC function was promoted by factors associated with Parkinsonian risk, including male sex, α-synuclein, DAT and a dorsolateral co-ordinate, but limited by factors associated with protection, that is, female sex, glucocerebrosidase activity, Calb1 and ventromedial co-ordinate. Together, these data show that LTCC function in DA axons and isradipine effect are locally governed and suggest they vary in a manner that in turn might impact on, or reflect, the cellular stress that leads to parkinsonian degeneration.
(© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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