β-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a β-Subunit-Like Fashion

Abstract

The ␤-secretase BACE1 is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease, but how its action on transmembrane proteins other than the amyloid precursor protein affects the nervous system is only beginning to be understood. We report here that BACE1 regulates neuronal excitability through an unorthodox, nonenzymatic interaction with members of the KCNQ (Kv7) family that give rise to the M-current, a noninactivating potassium current with slow kinetics. In hippocampal neurons from BACE1 Ϫ/Ϫ mice, loss of M-current enhanced neuronal excitability. We relate the diminished M-current to the previously reported epileptic phenotype of BACE1-deficient mice. In HEK293T cells, BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation. Biochemical evidence strongly suggested that BACE1 physically associates with channel proteins in a ␤-subunit-like fashion. Our results establish BACE1 as a physiologically essential constituent of regular M-current function and elucidate a striking new feature of how BACE1 impacts on neuronal activity in the intact and diseased brain.

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…104 Furthermore, the currentpromoting effect of BACE1 was different from that of the established M-current activator retigabine. 96 Taken together, these data suggest that the long-held view of M-current arising from neuronal KCNQ channel assemblies lacking auxiliary subunits requires modification. In the absence of KCNEs as binding partners for neuronal KCNQ channels, BACE1 may step in and become an essential constituent of M-current.…”

“…96 Co-expression of BACE1 increased KCNQ2/3 current amplitude, shifted activation to slightly more negative potentials, accelerated activation, and decelerated deactivation. Most importantly, the effects of BACE1 were non-proteolytic in nature, since they were reproduced by a proteolytically inactive BACE1 mutant.…”

“…96 In CA1 pyramidal neurons from wild type mice, depolarizing current injection elicited a train of action potentials (APs), which showed frequency adaption due to M-current activation. 90,97 By contrast, BACE1-deficient neurons fired APs at higher frequency (Fig.…”

“…Notably, BACE1 was also capable of increasing currents mediated by heterologously expressed KCNQ4 or KCNQ5. 96 Since the functionality of KCNQ channels strongly depends on adequate PIP 2 levels, an obvious question is whether BACE1, as it becomes part of KCNQ channel complexes, enhances their affinity for PIP 2 , thereby promoting channel openings. However, BACE1 did not alter the decrease of KCNQ2/3 currents upon PIP 2 depletion, nor did PIP 2 displace BACE1.…”

“…However, BACE1 did not alter the decrease of KCNQ2/3 currents upon PIP 2 depletion, nor did PIP 2 displace BACE1. 96,103 Thus, BACE1 appears to act differently than KCNE1, which sensitizes KCNQ1 to PIP 2 . 104 Furthermore, the currentpromoting effect of BACE1 was different from that of the established M-current activator retigabine.…”