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.
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).
Institute of Physiology and Pathophysiology, University of Erlangen-Nürnberg, Universitätsstr. 17, 91054, Erlangen, Germany. Tobias.Huth@physiologie1.med.uni-erlangen.de
Tobias
T
Huth
Andrea
A
Rittger
Paul
P
Saftig
Christian
C
Alzheimer
D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency / Q000502:physiology*; D002531:Cerebellum / Q000378:metabolism; D051379:Mice; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology*; D015222:Sodium Channels / Q000378:metabolism*; D062585:Voltage-Gated Sodium Channel beta-4 Subunit
C497241:Scn4b protein, mouse; D015222:Sodium Channels; D062585:Voltage-Gated Sodium Channel beta-4 Subunit; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
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