Ablation of P/Q-type Ca2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α(1A)-subunit

Kisun Jun, Erika S. Piedras-Rentería, Stephen M. Smith, David B. Wheeler, Seong Beom Lee, Taehoon G. Lee, Hemin Chin, Michael E. Adams, Richard H. Scheller, Richard W. Tsien, Hee Sup Shin

Research output: Contribution to journalArticlepeer-review

368 Scopus citations

Abstract

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).

Original languageEnglish (US)
Pages (from-to)15245-15250
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number26
DOIs
StatePublished - Dec 21 1999

ASJC Scopus subject areas

  • General

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