Ablation of P/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(1A)-subunit.
The Ca(2+) channel alpha(1A)-subunit is a voltage-gated, pore-forming membrane protein positioned at the intersection of two important lines of research: one exploring the diversity of Ca(2+) channels and their physiological roles, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and migraine. alpha(1A)-Subunits are thought to support both P- and Q-type Ca(2+) channel currents, but the most direct test, a null mutant, has not been described, nor is it known which changes in neurotransmission might arise from elimination of the predominant Ca(2+) delivery system at excitatory nerve terminals. We generated alpha(1A)-deficient mice (alpha(1A)(-/-)) and found that they developed a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying approximately 3-4 weeks after birth. P-type currents in Purkinje neurons and P- and Q-type currents in cerebellar granule cells were eliminated completely whereas other Ca(2+) channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in alpha(1A)(-/-) hippocampal slices persisted despite the lack of P/Q-type channels but showed enhanced reliance on N-type and R-type Ca(2+) entry. The alpha(1A)(-/-) mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in alpha(1A).
Jun
K
K
National Creative Research Initiatives Center for Calcium and Learning, Pohang University of Science and Technology, Pohang, Korea.
Piedras-Rentería
E S
ES
Smith
S M
SM
Wheeler
D B
DB
Lee
S B
SB
Lee
T G
TG
Chin
H
H
Adams
M E
ME
Scheller
R H
RH
Tsien
R W
RW
Shin
H S
HS
D000818:Animals; D001259:Ataxia; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000172:deficiency* / Q000235:genetics; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type / Q000378:metabolism*; D020907:Calcium Channels, Q-Type / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D004553:Electric Conductivity; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009422:Nervous System Diseases / Q000209:etiology; D011689:Purkinje Cells / Q000378:metabolism; D009435:Synaptic Transmission
D002118:Calcium; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D009419:Nerve Tissue Proteins