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 Ca2+ influx to Ca2+-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 Ca2+ 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12017-013-8234-1) contains supplementary material, which is available to authorized users.
Highlights
L-type voltage-gated calcium channels (LTCCs) fulfill important neurological functions, for example as neuronal pacemakers, in synaptic plasticity and excitation-transcription coupling (Striessnig et al 2006)
Statistical comparison of all events recorded within the 5-min test periods in this neuron showed that whereas small events showed no significant difference under the three experimental conditions, spike events were enhanced with high statistical significance (P value \0.001) in the presence of BayK 2.1-fold and were reduced with low statistical significance upon application of isradipine (P value \0.05) to 74 % of the control value in this particular neuron
Our earlier study demonstrated that bimodal LTCC coupling was only relevant at more long-lasting depolarizations, whereas shorter depolarizations were unequivocally enhanced by LTCC activity [as can be seen in supplementary recordings made in the presence of TTX (e.g., Figure B in Online Resource 3), early on during long-lasting depolarizations—for example within the first second—LTCC activity has enhancing effects, irrespective of the subsequent excitatory or inhibitory LTCC-mediated outcome]
Summary
L-type voltage-gated calcium channels (LTCCs) fulfill important neurological functions, for example as neuronal pacemakers, in synaptic plasticity and excitation-transcription coupling (Striessnig et al 2006). A gain of function mutation in Cav1.2 has been linked to Timothy syndrome, which involves neurological dysfunction such as developmental delay and autism (Bidaud and Lory 2011). Indirect evidence from earlier studies of this group indicates that the channel responsible for this alteration in calcium current is an LTCC (e.g., Amano et al 2001a and 2004). In neurons of the seizure prone gerbil, protein levels of Cav1.3 were found to be increased (Park et al 2003; Kang et al 2004). Similar to the above-named neurological dysfunctions, the incidence of epilepsies increases with age (Werhahn 2009)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
