Activity and calcium regulate nuclear targeting of the calcium channel beta4b subunit in nerve and muscle cells

Abstract

Auxiliary beta subunits are critical determinants of membrane expression and gating properties of voltage-gated calcium channels. Mutations in the beta4 subunit gene cause ataxia and epilepsy. However, the specific function of beta4 in neurons and its causal relation to neurological diseases are unknown. Here we report the localization of the beta4 subunit in the nuclei of cerebellar granule and Purkinje cells. beta4b was the only beta isoform showing nuclear targeting when expressed in neurons and skeletal myotubes. Its specific nuclear targeting property was mapped to an N-terminal double-arginine motif, which was necessary and sufficient for targeting beta subunits into the nucleus. Spontaneous electrical activity and calcium influx negatively regulated beta4b nuclear localization by a CRM-1-dependent nuclear export mechanism. The activity-dependent shuttling of beta4b into and out of the nucleus indicates a specific role of this beta subunit in neurons, in communicating the activity of calcium channels to the nucleus.