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

Hessler S, Zheng F, Hartmann S, Rittger A, Lehnert S, Voelkel M, Nissen M, Edelmann E, Saftig P, Schwake M, Huth T, et al. (2015)
Journal of Neuroscience 35(8): 3298-3311.

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The beta-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(-/-) 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 beta-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.
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Hessler S, Zheng F, Hartmann S, et al. beta-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a beta-Subunit-Like Fashion. Journal of Neuroscience. 2015;35(8):3298-3311.
Hessler, S., Zheng, F., Hartmann, S., Rittger, A., Lehnert, S., Voelkel, M., Nissen, M., et al. (2015). beta-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a beta-Subunit-Like Fashion. Journal of Neuroscience, 35(8), 3298-3311. doi:10.1523/JNEUROSCI.3127-14.2015
Hessler, S., Zheng, F., Hartmann, S., Rittger, A., Lehnert, S., Voelkel, M., Nissen, M., Edelmann, E., Saftig, P., Schwake, M., et al. (2015). beta-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a beta-Subunit-Like Fashion. Journal of Neuroscience 35, 3298-3311.
Hessler, S., et al., 2015. beta-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a beta-Subunit-Like Fashion. Journal of Neuroscience, 35(8), p 3298-3311.
S. Hessler, et al., “beta-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a beta-Subunit-Like Fashion”, Journal of Neuroscience, vol. 35, 2015, pp. 3298-3311.
Hessler, S., Zheng, F., Hartmann, S., Rittger, A., Lehnert, S., Voelkel, M., Nissen, M., Edelmann, E., Saftig, P., Schwake, M., Huth, T., Alzheimer, C.: beta-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a beta-Subunit-Like Fashion. Journal of Neuroscience. 35, 3298-3311 (2015).
Hessler, Sabine, Zheng, Fang, Hartmann, Stephanie, Rittger, Andrea, Lehnert, Sandra, Voelkel, Meike, Nissen, Matthias, Edelmann, Elke, Saftig, Paul, Schwake, Michael, Huth, Tobias, and Alzheimer, Christian. “beta-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a beta-Subunit-Like Fashion”. Journal of Neuroscience 35.8 (2015): 3298-3311.
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8 Citations in Europe PMC

Data provided by Europe PubMed Central.

KCNQ-Encoded Potassium Channels as Therapeutic Targets.
Barrese V, Stott JB, Greenwood IA., Annu Rev Pharmacol Toxicol 58(), 2018
PMID: 28992433
Modulation of Kv7 channels and excitability in the brain.
Greene DL, Hoshi N., Cell Mol Life Sci 74(3), 2017
PMID: 27645822
The Voltage Activation of Cortical KCNQ Channels Depends on Global PIP2 Levels.
Kim KS, Duignan KM, Hawryluk JM, Soh H, Tzingounis AV., Biophys J 110(5), 2016
PMID: 26958886
Ion channel regulation by β-secretase BACE1 - enzymatic and non-enzymatic effects beyond Alzheimer's disease.
Lehnert S, Hartmann S, Hessler S, Adelsberger H, Huth T, Alzheimer C., Channels (Austin) 10(5), 2016
PMID: 27253079
Functions of the Alzheimer's Disease Protease BACE1 at the Synapse in the Central Nervous System.
Munro KM, Nash A, Pigoni M, Lichtenthaler SF, Gunnersen JM., J Mol Neurosci 60(3), 2016
PMID: 27456313

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