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The Journal of Neuroscience, March 1, 2002, 22(5):1573-1582
Alternative Splicing of the  4 Subunit Has
 1 Subunit Subtype-Specific Effects on
Ca2+ Channel Gating
Thomas D.
Helton and
William A.
Horne
Department of Anatomy, Physiological Sciences, and Radiology, North
Carolina State University College of Veterinary Medicine, Raleigh,
North Carolina 27606
Ca2+ channel  subunits are important
molecular determinants of the kinetics and voltage dependence of
Ca2+ channel gating. Through direct interactions
with channel-forming  1 subunits, subunits enhance
expression levels, accelerate activation, and have variable effects on
inactivation. Four distinct subunit genes each encode five
homologous sequence domains (D1-5), three of which (D1, D3, and D5)
undergo alternative splicing. We have isolated from human spinal cord a
novel alternatively spliced 4 subunit containing a short
form of domain D1 (4a) that is highly homologous
to N termini of Xenopus and rat 3
subunits. The purpose of this study was to compare the gating
properties of various 1 subunit complexes containing
4a with those of complexes containing a 4
subunit with a longer form of domain D1, 4b. Expression
in Xenopus oocytes revealed that, relative to
1A and 1B complexes containing
4b, the voltage dependence of activation and
inactivation of complexes containing 4a were shifted to
more depolarized potentials. Moreover, 1A and
1B complexes containing 4a inactivated at
a faster rate. Interestingly, 4 subunit alternative splicing did not influence the gating properties of 1C
and 1E subunits. Experiments with 4
deletion mutants revealed that both the N and C termini of the
4 subunit play critical roles in setting voltage-dependent gating parameters and that their effects are 1 subunit specific. Our data are best explained by a
model in which distinct modes of activation and inactivation result
from -subunit splice variant-specific interactions with an
1 subunit gating structure.
Key words:
4 subunit; alternative splicing; N terminus; calcium
channel; gating; voltage clamp; spinal cord
Copyright © 2002 Society for Neuroscience 0270-6474/02/2251573-10$05.00/0
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