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: Lena Rubi, Ulla Schandl, Michael Lagler, Petra Geier, Daniel Spies, Kuheli Das Gupta, Stefan Boehm, Helmut Kubista
• Journal: Neuromolecular medicine (Neuromolecular Med) Vol. 15 Issue 3 Pg. 476-92 (Sep 2013) ISSN: 1559-1174 [Electronic] United States
• PMID: 23695859 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone
• Anthracenes
• Calcium Channels, L-Type
• Caffeine
• 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
• Hydrogen Peroxide
• 4-Aminopyridine
• Magnesium
• Isradipine
• Dimethyl Sulfoxide

Topics

• 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester (pharmacology)
• 4-Aminopyridine (pharmacology)
• Animals
• Anthracenes (pharmacology)
• Caffeine (pharmacology)
• Calcium Channels, L-Type (drug effects, physiology)
• Calcium Signaling (drug effects, physiology)
• Cells, Cultured
• Dimethyl Sulfoxide (pharmacology)
• Epilepsy (physiopathology)
• Excitatory Postsynaptic Potentials (drug effects, physiology)
• Hippocampus (cytology)
• Hydrogen Peroxide (toxicity)
• Isradipine (pharmacology)
• Magnesium (pharmacology)
• Neurons (physiology)
• Oxidative Stress
• Patch-Clamp Techniques
• Rats
• Rats, Sprague-Dawley