Universität zu Köln

Bock, Gabriella, Gebhart, Mathias, Scharinger, Anja, Jangsangthong, Wanchana, Busquet, Perrine, Poggiani, Chiara, Sartori, Simone, Mangoni, Matteo E., Sinnegger-Brauns, Martina J., Herzig, Stefan, Striessnig, Joerg ORCID: 0000-0002-9406-7120 and Koschak, Alexandra (2011). Functional Properties of a Newly Identified C-terminal Splice Variant of Ca(v)1.3 L-type Ca2+ Channels. J. Biol. Chem., 286 (49). S. 42736 - 42749. BETHESDA: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. ISSN 1083-351X

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Abstract

An intramolecular interaction between a distal (DCRD) and a proximal regulatory domain (PCRD) within theCterminus of long Ca(v)1.3 L-type Ca2+ channels (Cav1.3(L)) is a major determinant of their voltage-and Ca2+-dependent gating kinetics. Removal of these regulatory domains by alternative splicing generates Ca(v)1.3(42A) channels that activate at a more negative voltage range and exhibit more pronounced Ca2+-dependent inactivation. Here we describe the discovery of a novel short splice variant (Ca(v)1.3(43S)) that is expressed at high levels in the brain but not in the heart. It lacks the DCRD but, in contrast to Ca(v)1.3(42A), still contains PCRD. When expressed together with alpha 2 delta 1 and beta 3 subunits in tsA-201 cells, Ca(v)1.3(43S) also activated at more negative voltages like Ca(v)1.3(42A) but Ca2+-dependent inactivation was less pronounced. Single channel recordings revealed much higher channel open probabilities for both short splice variants as compared with Ca(v)1.3(L). The presence of the proximal C terminus in Ca(v)1.3(43S) channels preserved their modulation by distal C terminus-containing Ca(v)1.3- and Ca(v)1.2-derived C-terminal peptides. Removal of the C-terminal modulation by alternative splicing also induced a faster decay of Ca2+ influx during electrical activities mimicking trains of neuronal action potentials. Our findings extend the spectrum of functionally diverse Ca(v)1.3 L-type channels produced by tissue-specific alternative splicing. This diversity may help to fine tune Ca2+ channel signaling and, in the case of short variants lacking a functional C-terminal modulation, prevent excessive Ca2+ accumulation during burst firing in neurons. This may be especially important in neurons that are affected by Ca2+-induced neurodegenerative processes.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bock, Gabriella UNSPECIFIED UNSPECIFIED UNSPECIFIED Gebhart, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Scharinger, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Jangsangthong, Wanchana UNSPECIFIED UNSPECIFIED UNSPECIFIED Busquet, Perrine UNSPECIFIED UNSPECIFIED UNSPECIFIED Poggiani, Chiara UNSPECIFIED UNSPECIFIED UNSPECIFIED Sartori, Simone UNSPECIFIED UNSPECIFIED UNSPECIFIED Mangoni, Matteo E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sinnegger-Brauns, Martina J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herzig, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Striessnig, Joerg UNSPECIFIED orcid.org/0000-0002-9406-7120 UNSPECIFIED Koschak, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-483579
DOI:	10.1074/jbc.M111.269951
Journal or Publication Title:	J. Biol. Chem.
Volume:	286
Number:	49
Page Range:	S. 42736 - 42749
Date:	2011
Publisher:	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Place of Publication:	BETHESDA
ISSN:	1083-351X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GATED CALCIUM-CHANNEL; CA2+-DEPENDENT INACTIVATION; CONGENITAL DEAFNESS; DOPAMINE NEURONS; DOMAIN; SUBUNITS; REVEALS; CELLS; MODULATION; MECHANISMS Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48357