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Pflugers Arch. 2011 Mar;461(3):355-71. doi: 10.1007/s00424-010-0913-2. Epub 2011 Jan 19.

β-Site APP-cleaving enzyme 1 (BACE1) cleaves cerebellar Na+ channel β4-subunit and promotes Purkinje cell firing by slowing the decay of resurgent Na+ current.

Author information

1
Institute of Physiology and Pathophysiology, University of Erlangen-Nürnberg, Universitätsstr. 17, 91054, Erlangen, Germany. Tobias.Huth@physiologie1.med.uni-erlangen.de

Abstract

In cerebellar Purkinje cells, the β4-subunit of voltage-dependent Na(+) channels has been proposed to serve as an open-channel blocker giving rise to a "resurgent" Na(+) current (I (NaR)) upon membrane repolarization. Notably, the β4-subunit was recently identified as a novel substrate of the β-secretase, BACE1, a key enzyme of the amyloidogenic pathway in Alzheimer's disease. Here, we asked whether BACE1-mediated cleavage of β4-subunit has an impact on I (NaR) and, consequently, on the firing properties of Purkinje cells. In cerebellar tissue of BACE1-/- mice, mRNA levels of Na(+) channel α-subunits 1.1, 1.2, and 1.6 and of β-subunits 1-4 remained unchanged, but processing of β4 peptide was profoundly altered. Patch-clamp recordings from acutely isolated Purkinje cells of BACE1-/- and WT mice did not reveal any differences in steady-state properties and in current densities of transient, persistent, and resurgent Na(+) currents. However, I (NaR) was found to decay significantly faster in BACE1-deficient Purkinje cells than in WT cells. In modeling studies, the altered time course of I (NaR) decay could be replicated when we decreased the efficiency of open-channel block. In current-clamp recordings, BACE1-/- Purkinje cells displayed lower spontaneous firing rate than normal cells. Computer simulations supported the hypothesis that the accelerated decay kinetics of I (NaR) are responsible for the slower firing rate. Our study elucidates a novel function of BACE1 in the regulation of neuronal excitability that serves to tune the firing pattern of Purkinje cells and presumably other neurons endowed with I (NaR).

PMID:
21246381
DOI:
10.1007/s00424-010-0913-2
[Indexed for MEDLINE]

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