Universität zu Köln

Ortner, Nadine J., Bock, Gabriella, Dougalis, Antonios ORCID: 0000-0002-2139-1616, Kharitonova, Maria, Duda, Johanna, Hess, Simon, Tuluc, Petronel ORCID: 0000-0003-3660-6138, Pomberger, Thomas ORCID: 0000-0002-2292-1594, Stefanova, Nadia ORCID: 0000-0001-8188-639X, Pitterl, Florian, Ciossek, Thomas, Oberacher, Herbert ORCID: 0000-0002-0963-8268, Draheim, Henning J., Kloppenburg, Peter, Liss, Birgit and Striessnig, Joerg ORCID: 0000-0002-9406-7120 (2017). Lower Affinity of Isradipine for L-Type Ca2+ Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson's Disease. J. Neurosci., 37 (28). S. 6761 - 6778. WASHINGTON: SOC NEUROSCIENCE. ISSN 0270-6474

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Abstract

Ca2+ -influx through L-type Ca2+ -channels (LTCCs) is associated with activity-related stressful oscillations of Ca2+ levels within dopaminergic (DA) neurons in the substantia nigra (SN), which may contribute to their selective degeneration in Parkinson's disease (PD). LTCC blockers were neuroprotective in mouse neurotoxin models of PD, and isradipine is currently undergoing testing in a phase III clinical trial in early PD. We report no evidence for neuroprotection by in vivo pretreatment with therapeutically relevant isradipine plasma levels, or Ca(v)1.3 LTCC deficiency in 6-OHDA-treated male mice. To explain this finding, we investigated the pharmacological properties of human LTCCs during SN DA-like and arterial smooth muscle (aSM)-like activity patterns using whole-cell patch-clamp recordings in HEK293 cells (Ca(v)1.2 alpha 1-subunit, long and short Cav1.3 1-subunit splice variants; beta 3/alpha 2 delta 1). During SN DA-like pacemaking, only Ca(v)1.3 variants conducted Ca2+ current (I-Ca) at subthreshold potentials between action potentials. SN DA-like burst activity increased integrated I-Ca during (Ca(v)1.2 plus Ca(v)1.3) and after (Ca(v)1.3) the burst. Isradipine inhibition was splice variant and isoform dependent, with a 5to11-fold lower sensitivity to Ca(v)1.3 variants during SN DA-like pacemaking compared with Ca(v)1.2 during aSM-like activity. Supratherapeutic isradipineconcentrationsreducedthepacemakerprecisionofadultmouseSNDAneuronsbutdidnotaffecttheirsomaticCa(2+) oscillations. Our data predict that Ca(v)1.2 and Ca(v)1.3 splice variants contribute differentially to Ca2+ load inSNDAneurons, with prominent Ca(v)1.3-mediated ICa between action potentials and after bursts. The failure of therapeutically relevant isradipine levels to protectSNDAneurons can be explained by weaker state-dependent inhibition of SN DA LTCCs compared with aSM Ca(v)1.2.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ortner, Nadine J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bock, Gabriella UNSPECIFIED UNSPECIFIED UNSPECIFIED Dougalis, Antonios UNSPECIFIED orcid.org/0000-0002-2139-1616 UNSPECIFIED Kharitonova, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Duda, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Hess, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Tuluc, Petronel UNSPECIFIED orcid.org/0000-0003-3660-6138 UNSPECIFIED Pomberger, Thomas UNSPECIFIED orcid.org/0000-0002-2292-1594 UNSPECIFIED Stefanova, Nadia UNSPECIFIED orcid.org/0000-0001-8188-639X UNSPECIFIED Pitterl, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Ciossek, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Oberacher, Herbert UNSPECIFIED orcid.org/0000-0002-0963-8268 UNSPECIFIED Draheim, Henning J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kloppenburg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Liss, Birgit UNSPECIFIED UNSPECIFIED UNSPECIFIED Striessnig, Joerg UNSPECIFIED orcid.org/0000-0002-9406-7120 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-225029
DOI:	10.1523/JNEUROSCI.2946-16.2017
Journal or Publication Title:	J. Neurosci.
Volume:	37
Number:	28
Page Range:	S. 6761 - 6778
Date:	2017
Publisher:	SOC NEUROSCIENCE
Place of Publication:	WASHINGTON
ISSN:	0270-6474
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GATED CALCIUM-CHANNELS; VENTRAL TEGMENTAL AREA; K-ATP CHANNELS; FIRING PATTERN; MIDBRAIN NEURONS; D2-AUTORECEPTOR RESPONSES; SUBARACHNOID HEMORRHAGE; PACEMAKER FREQUENCY; CA(V)1.3 CHANNELS; STRIATAL LEVEL Multiple languages Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22502