title: A protein phosphatase 2calpha-Ca2+ channel complex for dephosphorylation of neuronal Ca2+ channels phosphorylated by protein kinase C.
abstract: Phosphorylation and dephosphorylation are primary means for rapid regulation of a variety of neuronal functions, such as membrane excitability, neurotransmitter release, and gene expression. Voltage-gated Ca2+ channels are targets for phosphorylation by a variety of second messengers through activation of different types of protein kinases (PKs). Protein phosphatases (PPs), like PKs, are equally important in regulating Ca2+ channels in neurons. However, much less is understood about whether and how a particular type of PP contributes to regulating neuronal Ca2+ channel activities. This is primarily because of the lack of specific inhibitors/activators for different types of PPs, particularly the PP2c family. The functional roles of PP2c and its substrates in the brain remain virtually unknown. During our yeast two-hybrid screening, PP2calpha was pulled out by both N- and P/Q-type Ca2+ channel C termini. This raised the possibility that PP2calpha might be associated with voltage-gated Ca2+ channels for regulation of the Ca(2+) channel activity. Biochemical studies show that PP2calpha binds directly to neuronal Ca2+ channels forming a functional protein complex in vivo. PP2calpha, unlike PP1, PP2a and PP2b, is more effective in dephosphorylation of neuronal Ca2+ channels after their phosphorylation by PKC. In hippocampal neurons, disruption of the PP2calpha-Ca2+ channel interaction significantly enhances the response of Ca2+ channels to modulation by PKC. Thus, the PP2calpha-Ca2+ channel complex is responsible for rapid dephosphorylation of Ca2+ channels and may contribute to regulation of synaptic transmission in neurons.
authors.affiliation: Department of Physiology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Li
authors.forename: Fushun
authors.initials: F
authors.lastname: Wang
authors.forename: Meizan
authors.initials: M
authors.lastname: Lai
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Ji-fang
authors.initials: JF
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020864:Calcium Channels, N-Type / Q000502:physiology*; D020865:Calcium Channels, P-Type / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured / Q000378:metabolism / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D006801:Humans; D017136:Ion Transport; D007668:Kidney; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D011493:Protein Kinase C / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D014162:Transfection
chemical_list: C491367:Cacna1a protein, rat; C503279:Cacna1b protein, rat; C504728:Cacna1c protein, rat; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D011493:Protein Kinase C; D002118:Calcium
references.citation: Mol Neurobiol. 1998 Oct;18(2):125-55
references.pmid: 10065877
references.citation: Cell Calcium. 1998 Nov-Dec;24(5-6):307-23
references.pmid: 10091001
references.citation: Neuron. 1999 Mar;22(3):549-58
references.pmid: 10197534
references.citation: Adv Second Messenger Phosphoprotein Res. 1999;33:3-22
references.pmid: 10218112
references.citation: Adv Second Messenger Phosphoprotein Res. 1999;33:131-51
references.pmid: 10218117
references.citation: Nature. 1999 May 13;399(6732):155-9
references.pmid: 10335845
references.citation: Nature. 1999 May 13;399(6732):159-62
references.pmid: 10335846
references.citation: Curr Opin Neurobiol. 1999 Jun;9(3):336-42
references.pmid: 10395578
references.citation: Physiol Rev. 2000 Jan;80(1):173-210
references.pmid: 10617768
references.citation: Genes Dev. 2000 May 1;14(9):1027-47
references.pmid: 10809663
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Sep;279(3):L429-38
references.pmid: 10956616
references.citation: Nature. 2000 Dec 7;408(6813):723-7
references.pmid: 11130074
references.citation: J Neurosci. 2001 May 1;21(9):2939-48
references.pmid: 11312277
references.citation: J Neurosci. 2001 May 1;21(9):2949-57
references.pmid: 11312278
references.citation: Science. 2001 Jul 6;293(5527):98-101
references.pmid: 11441182
references.citation: J Neurosci. 2001 Oct 1;21(19):7587-97
references.pmid: 11567049
references.citation: Annu Rev Pharmacol Toxicol. 2002;42:235-57
references.pmid: 11807172
references.citation: Nat Neurosci. 2002 Mar;5(3):210-7
references.pmid: 11865310
references.citation: Nat Cell Biol. 2002 Aug;4(8):E203-6
references.pmid: 12149635
references.citation: Nat Neurosci. 2003 May;6(5):468-75
references.pmid: 12665800
references.citation: Science. 2003 Apr 18;300(5618):445-52
references.pmid: 12702867
references.citation: Biochem J. 2003 Aug 1;373(Pt 3):641-59
references.pmid: 12749763
references.citation: Cell. 1992 Nov 27;71(5):713-6
references.pmid: 1423627
references.citation: Cell. 2003 Oct 3;115(1):37-48
references.pmid: 14532001
references.citation: J Biol Chem. 2004 Feb 6;279(6):4102-9
references.pmid: 14625305
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):16006-11
references.pmid: 14663150
references.citation: Science. 1989 Sep 29;245(4925):1474-80
references.pmid: 2506642
references.citation: Nature. 1986 May 8-14;321(6066):175-7
references.pmid: 3010137
references.citation: Trends Neurosci. 1994 Dec;17(12):531-6
references.pmid: 7532338
references.citation: Trends Neurosci. 1995 Feb;18(2):89-98
references.pmid: 7537420
references.citation: Exp Physiol. 1995 Jan;80(1):1-36
references.pmid: 7734129
references.citation: Science. 1994 Apr 1;264(5155):107-11
references.pmid: 7832825
references.citation: Arch Biochem Biophys. 1995 Feb 1;316(2):673-9
references.pmid: 7864622
references.citation: Neuron. 1994 Dec;13(6):1303-13
references.pmid: 7993624
references.citation: Neuron. 1993 Oct;11(4):751-7
references.pmid: 8104432
references.citation: Neuropharmacology. 1993 Nov;32(11):1075-88
references.pmid: 8107963
references.citation: Annu Rev Neurosci. 1994;17:551-67
references.pmid: 8210187
references.citation: J Biol Chem. 1993 Jan 5;268(1):133-7
references.pmid: 8380154
references.citation: Nature. 1993 Jan 14;361(6408):165-8
references.pmid: 8380626
references.citation: Neuron. 1993 Feb;10(2):127-36
references.pmid: 8382496
references.citation: Biochem Soc Trans. 1995 Aug;23(3):587-91
references.pmid: 8566422
references.citation: Neuron. 1996 Nov;17(5):991-1003
references.pmid: 8938130
references.citation: EMBO J. 1996 Dec 16;15(24):6798-809
references.pmid: 9003755
references.citation: Nature. 1997 Jan 30;385(6615):442-6
references.pmid: 9009192
references.citation: Nature. 1997 Jan 30;385(6615):446-50
references.pmid: 9009193
references.citation: Neuron. 1997 Jan;18(1):153-66
references.pmid: 9010213
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1512-6
references.pmid: 9037084
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8866-71
references.pmid: 9238069
references.citation: Trends Biochem Sci. 1997 Jul;22(7):245-51
references.pmid: 9255065
references.citation: J Neurosci. 1997 Sep 15;17(18):6929-38
references.pmid: 9278528
references.citation: Adv Second Messenger Phosphoprotein Res. 1997;31:159-81
references.pmid: 9344250
references.citation: Science. 1997 Dec 19;278(5346):2075-80
references.pmid: 9405336
references.citation: Biochem J. 1998 Feb 15;330 ( Pt 1):211-6
references.pmid: 9461512