Busquet, Perrine

Gebhart, Mathias

Juhasz-Vedres, Gabriella

Koschak, Alexandra

Poggiani, Chiara

Sartori, Simone B

Scharinger, Anja

Sinnegger-Brauns, Martina J

Striessnig, Jörg

BMC Pharmacology

English

PubMed

Gabriella Juhasz-Vedres

Anja Scharinger

Mathias Gebhart

Perrine Busquet

Chiara Poggiani

Simone B Sartori

Martina J Sinnegger-Brauns

Alexandra Koschak

Jörg Striessnig

Crossref

Identification of a new C-terminal splice variant of CaV1.3 L-type calcium channels with unique functional properties

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MEETING ABSTRACT Open Access
Identification of a new C-terminal splice variant
of CaV1.3 L-type calcium channels with unique
functional properties
Gabriella Juhasz-Vedres, Anja Scharinger, Mathias Gebhart, Perrine Busquet, Chiara Poggiani, Simone B Sartori,
Martina J Sinnegger-Brauns, Alexandra Koschak, Jörg Striessnig*
From 17th Scientific Symposium of the Austrian Pharmacological Society (APHAR). Joint meeting with the
Hungarian Society of Experimental and Clinical Pharmacology (MFT)
Innsbruck, Austria. 29-30 September 2011
Background
In L-type voltage-gated calcium channels (VGCCs) the
long C-terminal tail contains several sites for modulation
by protein-protein interaction. CaV1.3 VGCCs (CaV1.3L)
activate at negative voltages and support sinoatrial node
pacemaking and hearing, and shape neuronal excitability.
In CaV1.3L an intermolecular automodulatory C-terminal
interaction (CTM) has been described which affects
channel gating. CTM is characterized by interaction of a
distal C-terminal regulatory domain (DCRD) with a more
proximal regulatory domain (PCRD). If this CTM is
absent as in previously described short CaV1.342A, cal-
cium-dependent inactivation (CDI) increases and the
channel activation range shifts to more negative voltages
(i.e. “short” gating properties). Here we show that alter-
native splicing in exon 43 creates a new short splice var-
iant CaV1.343S found in human and mouse brain. It lacks
CTM, but still contains the PCRD motif, in contrast to
previously described CaV1.342A. Semiquantitative PCR
experiments showed that in mouse brain 39% of CaV1.3
channels contain exon 43S contrary to heart (6% 43S).
Methods and results
Biophysical analysis showed “short” gating properties for
CaV1.343S in both 15 mM and 2 mM external Ca
2+ when
co-expressed with b3 and a2δ-1 subunits in tsA-201 cells.
In 2 mM Ca2+ the inactivation rate of CaV1.343S was faster
for CaV1.3L, but slower for CaV1.342A (% inactivation after
100 ms at Vmax: CaV1.342A: 64.5 ± 3.5%; CaV1.343S: 52 ±
4.5%, CaV1.3L: 37.4 ± 3%, p < 0.001) by affecting the extent
of CDI. Due to a presence of PCRD, DCRD-containing
C-terminal fragments from CaV1.3 or CaV1.2 channels
could restore CaV1.3L gating behaviour. Indeed, co-expres-
sion of GFP-CaV1.2C349 fully restored long channel gating
properties in CaV1.343S (V0.5: CaV1.343S+GFP-CaV1.2C349:
1.37 ± 1.3 mV; CaV1.3L: −2.4 ± 0.6 mV). C-terminal spli-
cing also changed ICa kinetics during stimuli mimicking
trains of action potential waveforms, revealing a lower
total ICa during AP bursts in short splice variants.
Conclusions
Taken together, our data indicate that CaV1.3 C-terminal
splicing can serve as an important mechanism to fine-
tune the dynamics of calcium entry in neurons in an
activity dependent manner.
Acknowledgements
Supported by FWF P-20670 JS, P-22528 AK, and SFB F44.
Published: 5 September 2011
doi:10.1186/1471-2210-11-S2-A44
Cite this article as: Juhasz-Vedres et al.: Identification of a new C-
terminal splice variant of CaV1.3 L-type calcium channels with unique
functional properties. BMC Pharmacology 2011 11(Suppl 2):A44.
* Correspondence: joerg.striessnig@uibk.ac.at
Department of Pharmacology and Toxicology, Institute of Pharmacy, and
Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck,
6020 Innsbruck, Austria
Juhasz-Vedres et al. BMC Pharmacology 2011, 11(Suppl 2):A44
http://www.biomedcentral.com/1471-2210/11/S2/A44
© 2011 Juhasz-Vedres et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.


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Identification of a new C-terminal splice variant of CaV1.3 L-type calcium channels with unique functional properties

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