TY - JOUR
T1 - Ablation of P/Q-type Ca2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α(1A)-subunit
AU - Jun, Kisun
AU - Piedras-Rentería, Erika S.
AU - Smith, Stephen M.
AU - Wheeler, David B.
AU - Lee, Seong Beom
AU - Lee, Taehoon G.
AU - Chin, Hemin
AU - Adams, Michael E.
AU - Scheller, Richard H.
AU - Tsien, Richard W.
AU - Shin, Hee Sup
PY - 1999/12/21
Y1 - 1999/12/21
N2 - The Ca2+ channel α(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 Ca2+ channels and their physiological roles, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and migraine. α(1A)-Subunits are thought to support both P- and Q- type Ca2+ 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 Ca2+ delivery system at excitatory nerve terminals. We generated α(1A)-deficient mice (α(1A)(-/-)) and found that they developed a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying ≃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 Ca2+ channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in α(1A)(-/-) hippocampal slices persisted despite the lack of P/Q-type channels but showed enhanced reliance on N-type and R-type Ca2+ entry. The α(1A)(-/-) mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in α(1A).
AB - The Ca2+ channel α(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 Ca2+ channels and their physiological roles, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and migraine. α(1A)-Subunits are thought to support both P- and Q- type Ca2+ 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 Ca2+ delivery system at excitatory nerve terminals. We generated α(1A)-deficient mice (α(1A)(-/-)) and found that they developed a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying ≃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 Ca2+ channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in α(1A)(-/-) hippocampal slices persisted despite the lack of P/Q-type channels but showed enhanced reliance on N-type and R-type Ca2+ entry. The α(1A)(-/-) mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in α(1A).
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U2 - 10.1073/pnas.96.26.15245
DO - 10.1073/pnas.96.26.15245
M3 - Article
C2 - 10611370
AN - SCOPUS:0033593005
SN - 0027-8424
VL - 96
SP - 15245
EP - 15250
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -