title: Surface L-type Ca2+ channel expression levels are increased in aged hippocampus.
abstract: Age-related increase in L-type Ca(2+) channel (LTCC) expression in hippocampal pyramidal neurons has been hypothesized to underlie the increased Ca(2+) influx and subsequent reduced intrinsic neuronal excitability of these neurons that lead to age-related cognitive deficits. Here, using specific antibodies against Cav 1.2 and Cav 1.3 subunits of LTCCs, we systematically re-examined the expression of these proteins in the hippocampus from young (3 to 4 month old) and aged (30 to 32 month old) F344xBN rats. Western blot analysis of the total expression levels revealed significant reductions in both Cav 1.2 and Cav 1.3 subunits from all three major hippocampal regions of aged rats. Despite the decreases in total expression levels, surface biotinylation experiments revealed significantly higher proportion of expression on the plasma membrane of Cav 1.2 in the CA1 and CA3 regions and of Cav 1.3 in the CA3 region from aged rats. Furthermore, the surface biotinylation results were supported by immunohistochemical analysis that revealed significant increases in Cav 1.2 immunoreactivity in the CA1 and CA3 regions of aged hippocampal pyramidal neurons. In addition, we found a significant increase in the level of phosphorylated Cav 1.2 on the plasma membrane in the dentate gyrus of aged rats. Taken together, our present findings strongly suggest that age-related cognitive deficits cannot be attributed to a global change in L-type channel expression nor to the level of phosphorylation of Cav 1.2 on the plasma membrane of hippocampal neurons. Rather, increased expression and density of LTCCs on the plasma membrane may underlie the age-related increase in L-type Ca(2+) channel activity in CA1 pyramidal neurons.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
authors.forename: Félix Luis
authors.initials: FL
authors.lastname: Núñez-Santana
authors.forename: Myongsoo Matthew
authors.initials: MM
authors.lastname: Oh
authors.forename: Marcia Diana
authors.initials: MD
authors.lastname: Antion
authors.forename: Amy
authors.initials: A
authors.lastname: Lee
authors.forename: Johannes Wilhelm
authors.initials: JW
authors.lastname: Hell
authors.forename: John Francis
authors.initials: JF
authors.lastname: Disterhoft
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000918:Antibody Specificity; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D021122:Protein Subunits; D012333:RNA, Messenger; C093712:Cacna1d protein, rat; D010768:Phosphoserine
keywords: Cav1.2; Cav1.3; biotinylation; calcium; phosphorylation; qRT-PCR
references.citation: Trends Neurosci. 2006 Oct;29(10):587-99
references.pmid: 16942805
references.citation: Sci Signal. 2010 Sep 28;3(141):ra70
references.pmid: 20876873
references.citation: Neurobiol Aging. 1998 Nov-Dec;19(6):581-7
references.pmid: 10192218
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1990;14(4):525-51
references.pmid: 2236581
references.citation: Brain Res. 1988 Mar 29;445(1):137-41
references.pmid: 3365551
references.citation: Aging Cell. 2007 Jun;6(3):307-17
references.pmid: 17465978
references.citation: Cell. 2000 Jul 7;102(1):89-97
references.pmid: 10929716
references.citation: Learn Mem. 2008 Jan 03;15(1):1-5
references.pmid: 18174367
references.citation: J Physiol. 2006 Oct 1;576(Pt 1):87-102
references.pmid: 16809371
references.citation: J Neurosci. 1997 Jul 15;17(14):5334-48
references.pmid: 9204918
references.citation: Neurosci Lett. 2001 Apr 20;302(2-3):93-6
references.pmid: 11290395
references.citation: Neuron. 2013 May 8;78(3):483-97
references.pmid: 23664615
references.citation: J Neurosci. 2010 Apr 14;30(15):5125-35
references.pmid: 20392935
references.citation: J Neurosci. 2005 Mar 9;25(10):2609-16
references.pmid: 15758171
references.citation: Prog Brain Res. 1973;40(0):167-86
references.pmid: 4371053
references.citation: Am J Physiol. 1998 Jul;275(1):C1-24
references.pmid: 9688830
references.citation: Neuroscience. 2002;111(1):57-69
references.pmid: 11955712
references.citation: Neurobiol Aging. 1987 Jul-Aug;8(4):345-6
references.pmid: 3627349
references.citation: Neurobiol Aging. 2003 May-Jun;24 Suppl 1:S123-7; discussion S131
references.pmid: 12829120
references.citation: J Neurosci. 2007 Mar 21;27(12):3098-110
references.pmid: 17376971
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4357-62
references.pmid: 10759553
references.citation: Br J Pharmacol. 2001 Aug;133(7):988-96
references.pmid: 11487507
references.citation: Neuroscience. 2003;120(2):435-42
references.pmid: 12890513
references.citation: J Neurosci. 2000 Jul 15;20(14):5476-82
references.pmid: 10884331
references.citation: Learn Mem. 2006 Sep-Oct;13(5):584-9
references.pmid: 17015855
references.citation: Neurobiol Aging. 2010 Feb;31(2):328-38
references.pmid: 18471936
references.citation: Biochemistry. 1996 Aug 13;35(32):10392-402
references.pmid: 8756695
references.citation: Hippocampus. 2004;14(2):193-215
references.pmid: 15098725
references.citation: J Biol Chem. 2011 Apr 8;286(14):12627-39
references.pmid: 21224388
references.citation: Aging Cell. 2007 Jun;6(3):319-25
references.pmid: 17517041
references.citation: Science. 1984 Nov 30;226(4678):1089-92
references.pmid: 6494926
references.citation: Neurobiol Aging. 2001 Jan-Feb;22(1):1-8
references.pmid: 11164270
references.citation: Brain Res. 1987 Sep 1;419(1-2):112-8
references.pmid: 3676719
references.citation: Brain Res Mol Brain Res. 2005 Apr 27;135(1-2):104-11
references.pmid: 15857673
references.citation: J Neurochem. 2008 May;105(3):573-83
references.pmid: 18266933
references.citation: J Neurophysiol. 1992 Dec;68(6):2100-9
references.pmid: 1491260
references.citation: Science. 1996 May 17;272(5264):1017-20
references.pmid: 8638124
references.citation: J Neurosci. 2003 May 1;23(9):3807-19
references.pmid: 12736351
references.citation: Metab Brain Dis. 2008 Dec;23(4):399-409
references.pmid: 18770014
references.citation: Annu Rev Cell Dev Biol. 2000;16:521-55
references.pmid: 11031246
references.citation: Hippocampus. 2007;17(3):235-51
references.pmid: 17265461
references.citation: J Biol Chem. 2007 Nov 9;282(45):32877-89
references.pmid: 17823125
references.citation: J Neurophysiol. 2004 Jun;91(6):2437-44
references.pmid: 14762159
references.citation: J Neurosci Methods. 2003 May 30;125(1-2):159-66
references.pmid: 12763242
references.citation: J Neurosci. 1998 Apr 1;18(7):2321-34
references.pmid: 9502793
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):16018-23
references.pmid: 14665691
references.citation: J Neurosci. 2005 May 4;25(18):4649-58
references.pmid: 15872113
references.citation: Neurobiol Aging. 1987 Jul-Aug;8(4):346-7
references.pmid: 3627350
references.citation: J Gerontol A Biol Sci Med Sci. 1996 Jan;51(1):B54-9
references.pmid: 8548501
references.citation: Behav Neurosci. 1993 Aug;107(4):618-26
references.pmid: 8397866
references.citation: Learn Mem. 2008 Apr 25;15(5):326-34
references.pmid: 18441291
references.citation: Brain Res. 1990 Dec 3;535(1):119-30
references.pmid: 1705468
references.citation: J Neurosci. 1998 May 1;18(9):3171-9
references.pmid: 9547225
references.citation: J Neurosci. 2009 Apr 15;29(15):4750-5
references.pmid: 19369544
references.citation: J Neurocytol. 1974 Oct;3(4):405-29
references.pmid: 4373545
references.citation: Eur J Neurosci. 2004 May;19(10):2650-8
references.pmid: 15147299
references.citation: Brain Res Mol Brain Res. 2002 Nov 15;107(2):120-7
references.pmid: 12425941
references.citation: Can J Physiol Pharmacol. 1989 Apr;67(4):359-62
references.pmid: 2758376
references.citation: Ann N Y Acad Sci. 1994 Dec 15;747:1-11
references.pmid: 7847664
references.citation: Science. 1984 Dec 14;226(4680):1345-7
references.pmid: 6095454
references.citation: Nat Neurosci. 2011 Feb;14(2):173-80
references.pmid: 21186355
references.citation: J Neurophysiol. 2008 Oct;100(4):1897-908
references.pmid: 18715900
references.citation: J Neurosci. 2001 Jun 1;21(11):4066-73
references.pmid: 11356894
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Neuroscience. 2002;110(2):213-25
references.pmid: 11958864
references.citation: Hippocampus. 1994 Feb;4(1):11-7
references.pmid: 8061749
references.citation: Nat Neurosci. 2011 Aug 07;14(9):1109-11
references.pmid: 21822269
references.citation: Science. 1989 Feb 10;243(4892):809-11
references.pmid: 2916127
references.citation: J Biol Chem. 2012 Jun 29;287(27):22584-92
references.pmid: 22589548
references.citation: J Neurosci. 2006 Mar 29;26(13):3482-90
references.pmid: 16571755
references.citation: Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10135-9
references.pmid: 7694283
references.citation: J Cell Biol. 1993 Nov;123(4):949-62
references.pmid: 8227151
references.citation: J Biol Chem. 1994 Jan 21;269(3):1635-40
references.pmid: 7507480
references.citation: Neurobiol Aging. 1996 Jul-Aug;17(4):619-29
references.pmid: 8832637
references.citation: J Neurosci. 2009 Feb 11;29(6):1805-16
references.pmid: 19211887
references.citation: Peptides. 1986 Jan-Feb;7(1):155-9
references.pmid: 3520509