Boehm, Stefan

Geier, Petra

Kubista, Helmut

Lagler, Michael

BMC Pharmacology

English

PubMed

Petra Geier

Michael Lagler

Stefan Boehm

Helmut Kubista

Springer - Publisher Connector

L-type voltage-gated calcium channels in hippocampal neurons and their potential as anti-epilept(ogen)ic drug targets

BioMed CentralBMC Pharmacology
ssOpen AcceMeeting abstract
L-type voltage-gated calcium channels in hippocampal neurons and 
their potential as anti-epilept(ogen)ic drug targets
Petra Geier, Michael Lagler, Stefan Boehm and Helmut Kubista*
Address: Institute of Pharmacology, Centre for Biomolecular Medicine and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria
Email: Helmut Kubista* - helmut.kubista@meduniwien.ac.at
* Corresponding author    
Background
Neuronal L-type voltage-gated calcium channels (LTCCs)
were shown to be involved in the control of neuronal
excitability, synaptic plasticity and gene expression. These
mechanisms are altered in epileptic tissue and are thought
to contribute to epileptogenesis. Hence, LTCCs are inter-
esting targets for epileptic and anti-epileptic therapy.
However, their role in epilepsy, whether LTCCs enhance
or reduce epileptiform/epileptogenic activity, remained
unclear. The aim of this study was to identify in which
manner LTCCs contribute and/or modulate electrical exci-
tation.
Methods
Current-clamp experiments were performed on hippoc-
ampal neurons in culture using the perforated patch-
clamp method to record membrane voltage. The neurons
were continuously superfused and LTCC activity was
modulated by application of the dihydropyridines BayK
8644 (LTCC agonist) and isradipine (LTCC antagonist),
all in the presence of TTX. Electrical excitation was evoked
by incremental current injections, whereby the neurons
were depolarised experimentally beyond the LTCC activa-
tion threshold.
Results
With 8 s long depolarisations LTCC-mediated effects
appeared as bumps, oscillatory activity or hyperpolarising
sags. Using ion channel blockers and ion-exchange exper-
iments we provide evidence that LTCCs couple to both
SK(KCa2.x) and CAN (probably TRPM) channels, that
these couplings underlie the various LTCC-mediated
effects and show up as after-depolarisations (ADPs) or
after-hyperpolarisations (AHPs) following the current
pulse. These coupling modes operate in parallel, because
blocking one type of afterpotential uncovered the other.
Varying pulse length and current strength we obtained evi-
dence that ADPs are activated at a lower LTCC activity
than AHPs. Most notably, irrespective of the predominant
coupling mode leading to a depolarising or hyperpolaris-
ing modulation of the voltage responses, the initial effect
of LTCC activation (e.g. the one occurring within the first
second) was, in all cells, an enhancement of the depolari-
sations.
Conclusion
Varied predominance of LTCC coupling may explain the
controversy surrounding LTCC blockers as antiepileptic
drug targets. However, short excitatory signals were always
subject to LTCC-mediated augmentation. Brief (≤1 s),
excessive depolarisations (so-called paroxysmal depolari-
sation shifts or PDS) were recently implied as important
elements in epileptogenesis, appearing prior to actual sei-
zures, probably altering neuronal circuits by causing
repetitive, synchronised pulsative cytosolic Ca2+ rises. In
the framework of this hypothesis our data point to a
potential use of LTCC inhibitors to counteract PDS, and
hence epileptogenesis.
from 15th Scientific Symposium of the Austrian Pharmacological Society (APHAR) Joint meeting with the Hungarian Society of Experimental and Clinical 
Pharmacology (MFT) and the Slovenian Pharmacological Society (SDF)
Graz, Austria. 19-21 November 2009
Published: 12 November 2009
BMC Pharmacology 2009, 9(Suppl 2):A20 doi:10.1186/1471-2210-9-S2-A20
<supplement> <title> <p>15th Scientific Symposium of the Austrian Pharmacological Society (APHAR)</p> </title> <editor>Andrea Laslop and Thomas Griesbacher</editor> <note>Meeting abstracts - A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1471-2210-9-S2-full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/1471-2210-9-S2-info.pdf</url> </supplement>
This abstract is available from: http://www.biomedcentral.com/1471-2210/9/S2/A20
© 2009 Geier et al; licensee BioMed Central Ltd. Page 1 of 2
(page number not for citation purposes)
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Acknowledgements
Supported by FWF grant P19710.Page 2 of 2
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L-type voltage-gated calcium channels in hippocampal neurons and their potential as anti-epilept(ogen)ic drug targets

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