TY - JOUR
T1 - Mechanism of manganese dysregulation of dopamine neuronal activity
AU - Lin, Min
AU - Colon-Perez, Luis M.
AU - Sambo, Danielle O.
AU - Miller, Douglas R.
AU - Lebowitz, Joseph J.
AU - Jimenez-Rondan, Felix
AU - Cousins, Robert J.
AU - Horenstein, Nicole
AU - Aydemir, Tolunay Beker
AU - Febo, Marcelo
AU - Khoshbouei, Habibeh
N1 - Funding Information:
This work was supported by NIDA grants: NIDA-DA026947, NIDA-DA026947S1 and NIDA-DA043895; NINDA grant: NINDS-NS071122 NIH Office of Director: OD043895. We thank Dr. Gregory Hockerman for providing plasmids for Cav1.2-GFP and Cav1.3-GFP; Dr. Richard B. Silverman for providing HEK 293 cells stably expressing Cav1.2 or 1.3; and Dr. Robert Brenner for providing HEK293 cells stably expressing GFP-BK α subunits. Correspondence should be addressed to Habibeh Khoshbouei at Habibeh@ufl.edu. https://doi.org/10.1523/JNEUROSCI.2830-19.2020 Copyright © 2020 the authors
Publisher Copyright:
© 2020 Society for Neuroscience. All rights reserved.
PY - 2020/7/22
Y1 - 2020/7/22
N2 - Manganese exposure produces Parkinson's-like neurologic symptoms, suggesting a selective dysregulation of dopamine transmission. It is unknown, however, how manganese accumulates in dopaminergic brain regions or how it regulates the activity of dopamine neurons. Our in vivo studies in male C57BLJ mice suggest that manganese accumulates in dopamine neurons of the VTA and substantia nigra via nifedipine-sensitive Ca2+channels. Manganese produces a Ca2+channel-mediated current, which increases neurotransmitter release and rhythmic firing activity of dopamine neurons. These increases are prevented by blockade of Ca2+channels and depend on downstream recruitment of Ca2+-activated potassium channels to the plasma membrane. These findings demonstrate the mechanism of manganese-induced dysfunction of dopamine neurons, and reveal a potential therapeutic target to attenuate manganese-induced impairment of dopamine transmission.
AB - Manganese exposure produces Parkinson's-like neurologic symptoms, suggesting a selective dysregulation of dopamine transmission. It is unknown, however, how manganese accumulates in dopaminergic brain regions or how it regulates the activity of dopamine neurons. Our in vivo studies in male C57BLJ mice suggest that manganese accumulates in dopamine neurons of the VTA and substantia nigra via nifedipine-sensitive Ca2+channels. Manganese produces a Ca2+channel-mediated current, which increases neurotransmitter release and rhythmic firing activity of dopamine neurons. These increases are prevented by blockade of Ca2+channels and depend on downstream recruitment of Ca2+-activated potassium channels to the plasma membrane. These findings demonstrate the mechanism of manganese-induced dysfunction of dopamine neurons, and reveal a potential therapeutic target to attenuate manganese-induced impairment of dopamine transmission.
KW - Dopamine Neurons
KW - L-Type Calcium Channel
KW - Manganese
KW - Parkinson's Disease
KW - Synaptic Transmission
UR - http://www.scopus.com/inward/record.url?scp=85088492776&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2830-19.2020
DO - 10.1523/JNEUROSCI.2830-19.2020
M3 - Article
C2 - 32576620
AN - SCOPUS:85088492776
SN - 0270-6474
VL - 40
SP - 5871
EP - 5891
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 30
ER -