title: Alzheimer's secretases regulate voltage-gated sodium channels.
abstract: BACE1 and presenilin (PS)/γ-secretase are primary proteolytic enzymes responsible for the generation of pathogenic amyloid β-peptides (Aβ) in Alzheimer's disease. We and others have found that β-subunits of the voltage-gated sodium channel (Na(v)βs) also undergo sequential proteolytic cleavages mediated by BACE1 and PS/γ-secretase. In a follow-up study, we reported that elevated BACE1 activity regulates total and surface expression of voltage-gated sodium channels (Na(v)1 channels) and thereby modulates sodium currents in neuronal cells and mouse brains. In this review, we focus on the molecular mechanism of how BACE1 and PS/γ-secretase regulate Na(v)1 channels in neuronal cells. We will also discuss potential physiological and pathological roles of BACE1- and PS/γ-secretase-mediated processing of Na(v)βs in relation to Na(v)1 channel function.
authors.affiliation: Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Dora M
authors.initials: DM
authors.lastname: Kovacs
authors.forename: Manuel T
authors.initials: MT
authors.lastname: Gersbacher
authors.forename: Doo Yeon
authors.initials: DY
authors.lastname: Kim
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D009474:Neurons / Q000378:metabolism; D053763:Presenilins / Q000502:physiology; D015222:Sodium Channels / Q000096:biosynthesis*
chemical_list: D053763:Presenilins; D015222:Sodium Channels; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
references.citation: Nature. 1999 Dec 2;402(6761):537-40
references.pmid: 10591214
references.citation: J Neurosci. 2008 Mar 19;28(12):3246-56
references.pmid: 18354028
references.citation: Brain Res. 2004 May 29;1009(1-2):1-8
references.pmid: 15120577
references.citation: Brain Res. 2000 Dec 15;886(1-2):5-14
references.pmid: 11119683
references.citation: Biochem Biophys Res Commun. 2007 Sep 14;361(1):43-8
references.pmid: 17644063
references.citation: Nature. 2006 Oct 19;443(7113):768-73
references.pmid: 17051202
references.citation: J Biol Chem. 2005 Jun 17;280(24):23009-17
references.pmid: 15824102
references.citation: J Clin Psychiatry. 1996;57 Suppl 7:46-51; discussion 52-4
references.pmid: 8690697
references.citation: Cell. 2007 Oct 19;131(2):215-21
references.pmid: 17956719
references.citation: Neuron. 2000 Apr;26(1):13-25
references.pmid: 10798388
references.citation: Nature. 1999 Dec 2;402(6761):533-7
references.pmid: 10591213
references.citation: Neuron. 1996 Nov;17(5):1005-13
references.pmid: 8938131
references.citation: Mol Cell Neurosci. 1999 Dec;14(6):419-27
references.pmid: 10656250
references.citation: Prog Brain Res. 2007;161:195-203
references.pmid: 17618978
references.citation: Science. 2002 Oct 25;298(5594):789-91
references.pmid: 12399581
references.citation: J Neurochem. 2009 Feb;108(4):1045-56
references.pmid: 19196431
references.citation: Arch Neurol. 2009 Apr;66(4):435-40
references.pmid: 19204149
references.citation: Neuron. 2004 Apr 8;42(1):23-36
references.pmid: 15066262
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17072-7
references.pmid: 12481039
references.citation: J Cell Biol. 2005 Jan 17;168(2):291-302
references.pmid: 15642747
references.citation: Science. 1999 Oct 22;286(5440):735-41
references.pmid: 10531052
references.citation: Epilepsia. 2004 Jul;45(7):751-6
references.pmid: 15230697
references.citation: Cell Mol Life Sci. 2009 May;66(9):1534-55
references.pmid: 19189053
references.citation: J Neurosci. 2005 Dec 14;25(50):11693-709
references.pmid: 16354928
references.citation: Novartis Found Symp. 2002;241:206-18; discussion 218-32
references.pmid: 11771647
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5585-90
references.pmid: 18385378
references.citation: Science. 2002 Jul 19;297(5580):353-6
references.pmid: 12130773
references.citation: J Neurosci. 2008 Aug 27;28(35):8677-81
references.pmid: 18753368
references.citation: J Biol Chem. 2005 Jun 17;280(24):23251-61
references.pmid: 15833746
references.citation: Neuron. 2001 Sep 13;31(5):713-26
references.pmid: 11567612
references.citation: Curr Opin Neurol. 2002 Aug;15(4):445-50
references.pmid: 12151841
references.citation: Nat Cell Biol. 2007 Jul;9(7):755-64
references.pmid: 17576410
references.citation: J Neuropsychiatry Clin Neurosci. 2003 Spring;15(2):231-8
references.pmid: 12724467
references.citation: J Biol Chem. 2005 Sep 2;280(35):30797-806
references.pmid: 15987683
references.citation: Neuron. 2007 Jun 7;54(5):721-37
references.pmid: 17553422
references.citation: J Neurol. 2006 Feb;253(2):139-58
references.pmid: 16267640
references.citation: Neuron. 2007 Sep 6;55(5):697-711
references.pmid: 17785178
references.citation: FASEB J. 2008 Aug;22(8):2970-80
references.pmid: 18413858
references.citation: Neuroscientist. 2008 Dec;14(6):571-83
references.pmid: 18940784
references.citation: Neurology. 2004 Jun 8;62(11):1984-9
references.pmid: 15184601
references.citation: Neuron. 2008 Dec 26;60(6):988-1009
references.pmid: 19109907
references.citation: J Neurosci. 2005 Nov 23;25(47):10970-80
references.pmid: 16306410
references.citation: Annu Rev Neurosci. 2003;26:565-97
references.pmid: 12730322
references.citation: Nat Med. 2003 Jan;9(1):3-4
references.pmid: 12514700
references.citation: Biochem Biophys Res Commun. 2002 Dec 6;299(3):373-6
references.pmid: 12445809
references.citation: Nat Med. 2009 Apr;15(4):377-9
references.pmid: 19287391
references.citation: Nature. 2009 Jul 30;460(7255):632-6
references.pmid: 19641596
references.citation: Alzheimers Dement. 2010 Mar;6(2):158-94
references.pmid: 20298981
references.citation: J Neuropathol Exp Neurol. 2001 Dec;60(12):1137-52
references.pmid: 11764087
references.citation: Neurology. 1996 Mar;46(3):727-30
references.pmid: 8618673
references.citation: J Biol Chem. 2004 Apr 16;279(16):16044-9
references.pmid: 14761957
references.citation: J Neurosci. 2010 Jun 30;30(26):8819-29
references.pmid: 20592204
references.citation: J Neurosci. 2007 Apr 4;27(14):3639-49
references.pmid: 17409228
references.citation: Cell. 1993 Dec 17;75(6):1039-42
references.pmid: 8261505
references.citation: Mol Cell Neurosci. 2009 Feb;40(2):143-55
references.pmid: 19013247
references.citation: Neurobiol Dis. 2009 Feb;33(2):282-9
references.pmid: 19056495
references.citation: J Neurochem. 2001 Mar;76(6):1871-8
references.pmid: 11259505
references.citation: Neurology. 2001 Jun 26;56(12):1621-7
references.pmid: 11428390
references.citation: J Biol Chem. 2004 Dec 3;279(49):51424-32
references.pmid: 15452131
references.citation: Nat Neurosci. 2006 Dec;9(12):1520-5
references.pmid: 17099708
references.citation: Nat Rev Neurosci. 2006 Dec;7(12):932-41
references.pmid: 17115075
references.citation: Arch Neurol. 2002 Sep;59(9):1381-9
references.pmid: 12223024
references.citation: Cell. 1997 May 16;89(4):629-39
references.pmid: 9160754
references.citation: J Neurosci. 2001 Oct 1;21(19):7517-25
references.pmid: 11567041
references.citation: Neurology. 1986 Sep;36(9):1226-30
references.pmid: 3092131
references.citation: Front Biosci. 2002 Jan 01;7:12-23
references.pmid: 11779698
references.citation: Nature. 1996 Sep 26;383(6598):307-8
references.pmid: 8848042
references.citation: J Biol Chem. 1999 Sep 10;274(37):26511-7
references.pmid: 10473612
references.citation: Science. 2006 Oct 27;314(5799):664-6
references.pmid: 16990514
references.citation: Neuroscientist. 2001 Feb;7(1):42-54
references.pmid: 11486343
references.citation: J Biol Chem. 2000 Apr 14;275(15):11383-8
references.pmid: 10753953
references.citation: J Neurosci. 2009 Oct 14;29(41):12787-94
references.pmid: 19828790