Ablation of P/Q-Type Ca2+ Channel Currents, Altered Synaptic Transmission, and Progressive Ataxia in Mice Lacking the α 1A-Subunit
Abstract
The Ca2+ channel α1A-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. α1A-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 α1A-deficient mice (α1A-/-) 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 α1A-/- hippocampal slices persisted despite the lack of P/Q-type channels but showed enhanced reliance on N-type and R-type Ca2+ entry. The α1A-/- mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in α1A.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- December 1999
- DOI:
- 10.1073/pnas.96.26.15245
- Bibcode:
- 1999PNAS...9615245J