Functional Properties of a Newly Identified C-terminal Splice Variant of Cav1.3 L-type Ca2+ Channels

• Published in: The Journal of biological chemistry 2011-12, Vol.286 (49), p.42736-42748
• Main Authors: Bock, Gabriella, Gebhart, Mathias, Scharinger, Anja, Jangsangthong, Wanchana, Busquet, Perrine, Poggiani, Chiara, Sartori, Simone, Mangoni, Matteo E., Sinnegger-Brauns, Martina J., Herzig, Stefan, Striessnig, Jörg, Koschak, Alexandra
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Biophysics - methods; Brain - metabolism; Calcium - chemistry; Calcium Channels; Calcium Channels, L-Type - chemistry; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Calcium Signaling; CaV1.3; Cell Biology; Cell Line; Cell Signaling; Cellular Excitability Ion Channels; Cloning, Molecular; HEK293 Cells; Humans; Ion Channels; Ions; L-type Calcium Channels Alternative Splicing; Neurons - metabolism; Patch-Clamp Techniques; Protein Structure, Tertiary; RNA - metabolism; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.269951

An intramolecular interaction between a distal (DCRD) and a proximal regulatory domain (PCRD) within the C terminus of long Cav1.3 L-type Ca2+ channels (Cav1.3L) is a major determinant of their voltage- and Ca2+-dependent gating kinetics. Removal of these regulatory domains by alternative splicing generates Cav1.342A 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 (Cav1.343S) that is expressed at high levels in the brain but not in the heart. It lacks the DCRD but, in contrast to Cav1.342A, still contains PCRD. When expressed together with α2δ1 and β3 subunits in tsA-201 cells, Cav1.343S also activated at more negative voltages like Cav1.342A but Ca2+-dependent inactivation was less pronounced. Single channel recordings revealed much higher channel open probabilities for both short splice variants as compared with Cav1.3L. The presence of the proximal C terminus in Cav1.343S channels preserved their modulation by distal C terminus-containing Cav1.3- and Cav1.2-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 Cav1.3 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.