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The Journal of Neuroscience, July 1, 1999, 19(13):5322-5331
Alternative Splicing of a Short Cassette Exon in
 1B Generates Functionally Distinct N-Type Calcium
Channels in Central and Peripheral Neurons
Zhixin
Lin,
Yingxin
Lin,
Stephanie
Schorge,
Jennifer Qian
Pan,
Michael
Beierlein, and
Diane
Lipscombe
Department of Neuroscience, Brown University, Providence, Rhode
Island 02912
The N-type Ca channel  1B subunit is localized to
synapses throughout the nervous system and couples excitation to
release of neurotransmitters. In a previous study, two functionally
distinct variants of the 1B subunit were identified,
rn1B-b and rn1B-d, that differ at
two loci;four amino acids [SerPheMetGly (SFMG)] in IIIS3-S4 and two
amino acids [GluThr (ET)] in IVS3-S4. These variants are
reciprocally expressed in rat brain and sympathetic ganglia (Lin et
al., 1997a). We now show that the slower activation kinetics of
rn1B-b ( SFMG/+ET) compared with rn1B-d
(+SFMG/ET) channels are fully accounted for by the insertion of ET
in IVS3-S4 and not by the lack of SFMG in IIIS3-S4. We also show that
the inactivation kinetics of these two variants are indistinguishable. Through genomic analysis we identify a six-base cassette exon that
encodes the ET site and with ribonuclease protection assays demonstrate
that the expression of this mini-exon is essentially restricted to
1B RNAs of peripheral neurons. We also show evidence for
regulated alternative splicing of a six-base exon encoding NP in the
IVS3-S4 linker of the closely related 1A gene and
establish that residues NP can functionally substitute for ET in domain IVS3-S4 of 1B. The selective expression of functionally
distinct Ca channel splice variants of 1B and
1A subunits in different regions of the nervous system
adds a new dimension of diversity to voltage-dependent Ca signaling in
neurons that may be important for optimizing action potential-dependent
transmitter release at different synapses.
Key words:
N-type calcium channel; regulated alternative splicing; S3-S4 linker; genomic analysis; P/Q-type calcium channel; calcium
channel 1 subunits
Copyright © 1999 Society for Neuroscience 0270-6474/99/19135322-10$05.00/0
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