title: Raised activity of L-type calcium channels renders neurons prone to form paroxysmal depolarization shifts.
abstract: Neuronal L-type voltage-gated calcium channels (LTCCs) are involved in several physiological functions, but increased activity of LTCCs has been linked to pathology. Due to the coupling of LTCC-mediated Ca(2+) influx to Ca(2+)-dependent conductances, such as KCa or non-specific cation channels, LTCCs act as important regulators of neuronal excitability. Augmentation of after-hyperpolarizations may be one mechanism that shows how elevated LTCC activity can lead to neurological malfunctions. However, little is known about other impacts on electrical discharge activity. We used pharmacological up-regulation of LTCCs to address this issue on primary rat hippocampal neurons. Potentiation of LTCCs with Bay K8644 enhanced excitatory postsynaptic potentials to various degrees and eventually resulted in paroxysmal depolarization shifts (PDS). Under conditions of disturbed Ca(2+) homeostasis, PDS were evoked frequently upon LTCC potentiation. Exposing the neurons to oxidative stress using hydrogen peroxide also induced LTCC-dependent PDS. Hence, raising LTCC activity had unidirectional effects on brief electrical signals and increased the likeliness of epileptiform events. However, long-lasting seizure-like activity induced by various pharmacological means was affected by Bay K8644 in a bimodal manner, with increases in one group of neurons and decreases in another group. In each group, isradipine exerted the opposite effect. This suggests that therapeutic reduction in LTCC activity may have little beneficial or even adverse effects on long-lasting abnormal discharge activities. However, our data identify enhanced activity of LTCCs as one precipitating cause of PDS. Because evidence is continuously accumulating that PDS represent important elements in neuropathogenesis, LTCCs may provide valuable targets for neuroprophylactic therapy.
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Waehringerstrasse 13a, 1090, Vienna, Austria.
authors.forename: Lena
authors.initials: L
authors.lastname: Rubi
authors.forename: Ulla
authors.initials: U
authors.lastname: Schandl
authors.forename: Michael
authors.initials: M
authors.lastname: Lagler
authors.forename: Petra
authors.initials: P
authors.lastname: Geier
authors.forename: Daniel
authors.initials: D
authors.lastname: Spies
authors.forename: Kuheli Das
authors.initials: KD
authors.lastname: Gupta
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehm
authors.forename: Helmut
authors.initials: H
authors.lastname: Kubista
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004827:Epilepsy / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D006861:Hydrogen Peroxide / Q000633:toxicity; D017275:Isradipine / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D020746:Calcium Channels, L-Type; D002110:Caffeine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D006861:Hydrogen Peroxide; D015761:4-Aminopyridine; D008274:Magnesium; D017275:Isradipine; D004121:Dimethyl Sulfoxide