PMID:9742139

Citation	Dove, LS, Abbott, LC and Griffith, WH (1998) Whole-cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice. J. Neurosci. 18:7687-99
Abstract	The leaner (tgla) mutation in mice results in severe ataxia and an overt neurodegeneration of the cerebellum. Positional cloning has revealed that the tgla mutation occurs in a gene encoding the voltage-activated calcium channel alpha1A subunit. The alpha1A subunit is highly expressed in the cerebellum and is thought to be the pore-forming subunit of P- and Q-type calcium channels. In this study we used both whole-cell and single-channel patch-clamp recordings to examine the functional consequences of the tgla mutation on P-type calcium currents. High-voltage-activated (HVA) calcium currents were recorded from acutely dissociated cerebellar Purkinje cells of homozygous leaner (tgla/tgla) and age-matched wild-type (+/+) mice. In whole cell recordings, we observed a marked reduction of peak current density in tgla/tgla Purkinje cells (-35.0 +/- 1.8 pA/pF) relative to that in +/+ (-103.1 +/- 5.9 pA/pF). The reduced whole-cell current in tgla/tgla cells was accompanied by little to no alteration in the voltage dependence of channel gating. In both genotypes, HVA currents were predominantly of the omega-agatoxin-IVA-sensitive P-type. Cell-attached patch-clamp recordings revealed no differences in single-channel conductance between the two genotypes and confirmed the presence of three distinct conductance levels (9, 13-14, and 17-18 pS) in cerebellar Purkinje cells. Analysis of patch open-probability (NPo) revealed a threefold reduction in the open-probability of channels in tgla/tgla patches (0.04 +/- 0.01) relative to that in +/+ (0.13 +/- 0.02), which may account for the reduced whole-cell current in tgla/tgla Purkinje cells. These results suggest that the tgla mutation can alter native P-type calcium channels at the single-channel level and that these alterations may contribute to the neuropathology of the leaner phenotype.
Links	PubMed
Keywords	Animals; Body Weight/physiology; Calcium Channel Blockers/pharmacology; Calcium Channels/genetics; Calcium Channels/metabolism; Calcium Channels, N-Type; Electric Conductivity; Electric Stimulation; Female; Ion Channel Gating/drug effects; Ion Channel Gating/physiology; Male; Membrane Potentials/drug effects; Membrane Potentials/physiology; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Mutation/physiology; Nifedipine/pharmacology; Patch-Clamp Techniques; Peptides/pharmacology; Probability; Purkinje Cells/chemistry; Purkinje Cells/physiology; Spider Venoms/pharmacology; omega-Agatoxin IVA; omega-Conotoxin GVIA
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