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

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Abstract
Insights into the pathogenesis of migraine with aura may be gained from a study of human Ca(V)2.1 channels containing mutations linked to familial hemiplegic migraine (FHM). Here, we extend the previous single-channel analysis to human Ca(V)2.1 channels containing mutation V1457L. This mutation increased the channel open probability by shifting its activation to more negative voltages and reduced both the unitary conductance and the density of functional channels in the membrane. To investigate the possibility of changes in Ca(V)2.1 function common to all FHM mutations, we calculated the product of single-channel current and open probability as a measure of Ca(2+) influx through single Ca(V)2.1 channels. All five FHM mutants analyzed showed a single-channel Ca(2+) influx larger than wild type in a broad voltage range around the threshold of activation. We also expressed the FHM mutants in cerebellar granule cells from Ca(V)2.1alpha(1)-/- mice rather than HEK293 cells. The FHM mutations invariably led to a decrease of the maximal Ca(V)2.1 current density in neurons. Current densities were similar to wild type at lower voltages because of the negatively shifted activation of FHM mutants. Our data show that mutational changes of functional channel densities can be different in different cell types, and they uncover two functional effects common to all FHM mutations analyzed: increase of single-channel Ca(2+) influx and decrease of maximal Ca(V)2.1 current density in neurons. We discuss the relevance of these findings for the pathogenesis of migraine with aura.