Ablation of P/Q-type Ca 2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α 1A -subunit

作者：Kisun Jun, Erika S. Piedras-Renterı́a, Stephen M. Smith, David B. Wheeler, Seong‐Beom Lee, Taehoon G. Lee, Hemin R. Chin, Michael E. Adams, Richard H. Scheller, Richard W. Tsien, Hee‐Sup Shin · 发表于：Proceedings of the National Academy of Sciences · 年份：1999 · DOI：10.1073/pnas.96.26.15245 · 被引用次数：471 · 研究领域：Ion channel regulation and function、Genetic Neurodegenerative Diseases、Neuroscience and Neuropharmacology Research

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).