Single Tottering Mutations Responsible for the Neuropathic Phenotype of the P-type Calcium Channel

Abstract

Besides the same change, those of the tg la mice showed a more distinct change in voltage dependence of activation and inactivation, being shifted in the depolarizing direction by ϳ10 mV, with a broader voltage dependence of inactivation. In the recombinant expression system, the tg channel with a missense mutation (P601L) and one form of the two possible tg la aberrant splicing products, tg la (short) channel, showed a significant reduction in current density, while the other form of the tg la channels, tg la (long), had a current density comparable to the normal control. On the other hand, the shift in voltage dependence of activation and inactivation was observed only for the tg la (long) channel. Comparison of properties of the native and recombinant mutant channels suggests that single tottering mutations are directly responsible for the neuropathic phenotypes of reduction in current density and deviations in gating behavior, which lead to neuronal death and cerebellar atrophy.

Familial hemiplegic migraine mutations increase Ca 2+ influx through single human Ca V 2.1 channels and decrease maximal Ca V 2.1 current density in neurons

“…Tg la mutants also showed a slower velocity and frequent failure of propagation of CSD and a much larger reduction of excitatory with respect to inhibitory neurotransmitter release. It has been shown that tg and tg la mutations lead to a decreased P͞Q current density in both native cerebellar neurons and in heterologous expression systems, and that the tg la mutation shifts the activation curve of Ca V 2.1 channels to depolarized voltages and reduces their singlechannel open probability (26)(27)(28). These data support the conclusion that a reduced Ca 2ϩ entry through Ca V 2.1 channels reduces neuronal cortical network excitability and makes the cortex more resistant to CSD.…”

Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant Ca V 2.1 channels

“…Peak current amplitude during the test pulse was normalized and plotted against conditioning pulse voltage to generate the curves in C. phenotype in the relatively short life span of the mouse (17,(20)(21)(22). The absence of motor phenotype in heterozygous or homozygous Sca6 30Q mice also appears to support the notion that SCA6 is not a simple channelopathy because previously described loss-of-function Cacna1a mutants often show early-onset motor phenotypes associated with distinct alterations of Ca 2ϩ channel properties (23,24).…”

Expression of N-type calcium channels in human adrenocortical cells and their contribution to corticosteroid synthesis

“…26 Patch pipettes were made from borosilicate glass capillaries (1.5 mm outer diameter, 0.87 mm inner diameter; Hilgenberg, Malsfeld, Germany) using a P-97 Flaming/Brown micropipette puller (Sutter Instrument, Novato, CA, USA). Pipette resistance ranged from 2.5 to 3.5 MO when filled with the pipette solutions as described below.…”