Open AccessAblation of P/Q-type Ca 2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α 1A -subunit
Author(s) -
Kisun Jun,
Erika S. Piedras-Renterı́a,
Smith Sa,
David B. Wheeler,
Seong Beom Lee,
Taehoon G. Lee,
Hemin Chin,
Michael E. Adams,
Richard H. Scheller,
Richard W. Tsien,
Hee Sup Shin
Publication year - 1999
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.96.26.15245
Subject(s) - neurotransmission , neuroscience , excitatory postsynaptic potential , hippocampal formation , voltage dependent calcium channel , chemistry , biophysics , biology , medicine , biochemistry , inhibitory postsynaptic potential , receptor , calcium
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).