title: A concerted action of L- and T-type Ca(2+) channels regulates locus coeruleus pacemaking.
abstract: Dysfunction of noradrenergic locus coeruleus (LC) neurons is involved in psychiatric and neurodegenerative diseases and is an early hallmark of Parkinson's disease (PD). The analysis of ion channels underlying the autonomous electrical activity of LC neurons, which is ultimately coupled to cell survival signaling pathways, can lead to a better understanding of the vulnerability of these neurons. In LC neurons somatodendritic Ca(2+) oscillations, mediated by L-type Ca(2+) channels, accompany spontaneous spiking and are linked to mitochondrial oxidant stress. However, the expression and functional implication of low-threshold activated T-type Ca(2+) channels in LC neurons were not yet studied. To this end we performed RT-PCR expression analysis in LC neurons. In addition, we utilized slice patch clamp recordings of in vitro brainstem slices in combination with L-type and T-type Ca(2+) channel blockers. We found the expression of a distinct set of L-type and T-type Ca(2+) channel subtypes mediating a pronounced low-threshold activated Ca(2+) current component. Analyzing spike trains, we revealed that neither L-type Ca(2+) channel nor T-type Ca(2+) channel blockade alone leads to a change in firing properties. In contrast, a combined application of antagonists significantly decreased the afterhyperpolarization amplitude, resulting in an increased firing frequency. Hence, we report the functional expression of T-type Ca(2+) channels in LC neurons and demonstrate their role in increasing the robustness of LC pacemaking by working in concert with Cav1 channels.
authors: Institut für Physiologie und Pathophysiologie, Abteilung Vegetative Physiologie, Universität Marburg, 35037 Marburg, Germany.
authors: Lina A
authors: LA
authors: Matschke
authors: Institut für Anatomie und Zellbiologie, Medizinische Zellbiologie, Universität Marburg, 35037 Marburg, Germany.
authors: Mirjam
authors: M
authors: Bertoune
authors: Institut für Neurophysiologie, Neuroscience Center, 60590 Frankfurt, Germany.
authors: Jochen
authors: J
authors: Roeper
authors: Michael Smith Laboratories, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors: Terrance P
authors: TP
authors: Snutch
authors: Klinik für Neurologie, Philipps Universität Marburg, 35037 Marburg, Germany; Charitable Hertie Foundation, Frankfurt/Main, Germany.
authors: Wolfgang H
authors: WH
authors: Oertel
authors: Institut für Physiologie und Pathophysiologie, Abteilung Vegetative Physiologie, Universität Marburg, 35037 Marburg, Germany.
authors: Susanne
authors: S
authors: Rinné
authors: Institut für Physiologie und Pathophysiologie, Abteilung Vegetative Physiologie, Universität Marburg, 35037 Marburg, Germany. Electronic address: decher@staff.uni-marburg.de.
authors: Niels
authors: N
authors: Decher
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001703:Biophysics; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026941:Sodium Channel Blockers / Q000494:pharmacology; D018709:Statistics, Nonparametric; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D026941:Sodium Channel Blockers; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin
keywords: Isradipine; L- and T-type voltage gated Ca(2+) channels; Locus coeruleus; Mibefradil; Parkinson's disease; Z944