Mutations in the PSEN1 gene encoding presenilin-1 (PS1) protein are the most common cause of familial Alzheimer’s disease. One of these, deletion of exon 9, results in the production of shortened PS1 protein (PS1ΔE9). Neuronal hyperexcitability and hyperactivation of L-type calcium channels were observed in cellular and animal models of familial Alzheimer’s disease. However, the effect of PS1ΔE9 on L-type calcium channels has not been studied before. We demonstrate enhanced calcium entry through L-type calcium channels in hippocampal mouse neurons with exogenous expression of PS1ΔE9. Additionally, we show that the same effect of the exogenous PS1ΔE9 can be observed in cells with predominant expression of L-type calcium channels subunit Cav1.2. Further research is required to unravel molecular mechanisms underlying hyperactivation L-type calcium channels caused by PS1ΔE9 expression.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Chong CM, Ke M, Tan Y, Huang Z, Zhang K, Ai N, Ge W, Qin D, Lu JH, Su H. Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing γ-secretase-independent ERK/CREB signaling. Cell Death Dis. 2018;9(9):879. doi: https://doi.org/10.1038/s41419-018-0945-7
Coon AL, Wallace DR, Mactutus CF, Booze RM. L-type calcium channels in the hippocampus and cerebellum of Alzheimer’s disease brain tissue. Neurobiol. Aging. 1999;20(6):597-603. doi: https://doi.org/10.1016/s0197-4580(99)00068-8
Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum. Mol. Genet. 2004;13(2):159-170. doi: https://doi.org/10.1093/hmg/ddh019
Kabir MT, Uddin MS, Setu JR, Ashraf GM, Bin-Jumah MN, Abdel-Daim MM. Exploring the role of PSEN mutations in the pathogenesis of Alzheimer’s disease. Neurotox. Res. 2020;38(4):833-849. doi: https://doi.org/10.1007/s12640-020-00232-x
Lerdkrai C, Asavapanumas N, Brawek B, Kovalchuk Y, Mojtahedi N, Olmedillas Del Moral M, Garaschuk O. Intracellular Ca2+ stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA. 2018;115(6):E1279-E1288. doi: https://doi.org/10.1073/pnas.1714409115
Ryazantseva M, Goncharova A, Skobeleva K, Erokhin M, Methner A, Georgiev P, Kaznacheyeva E. Presenilin-1 delta E9 mutant induces STIM1-driven store-operated calcium channel hyperactivation in hippocampal neurons. Mol. Neurobiol. 2018;55(6):4667-4680. doi: https://doi.org/10.1007/s12035-017-0674-4
Ryazantseva M, Skobeleva K, Glushankova L, Kaznacheyeva E. Attenuated presenilin-1 endoproteolysis enhances storeoperated calcium currents in neuronal cells. J. Neurochem. 2016;136(5):1085-1095. doi: https://doi.org/10.1111/jnc.13495
Schampel A, Kuerten S. Danger: high voltage — the role of voltage-gated calcium channels in central nervous system pathology. Cells. 2017;6(4):43. doi: https://doi.org/10.3390/cells6040043
Stargardt A, Swaab DF, Bossers K. Storm before the quiet: neuronal hyperactivity and Aβ in the presymptomatic stages of Alzheimer’s disease. Neurobiol. Aging. 2015;36(1):1-11. doi: https://doi.org/10.1016/j.neurobiolaging.2014.08.014
Thibault O, Pancani T, Landfield PW, Norris CM. Reduction in neuronal L-type calcium channel activity in a double knock-in mouse model of Alzheimer’s disease. Biochim. Biophys. Acta. 2012;1822(4):546-549. doi: https://doi.org/10.1016/j.bbadis.2012.01.004
Tong BC, Lee CS, Cheng WH, Lai KO, Foskett JK, Cheung KH. Familial Alzheimer’s disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair storeoperated Ca2+ entry. Sci. Signal. 2016;9:ra89. doi: https://doi.org/10.1126/scisignal.aaf1371
Wang X, Zheng W. Ca2+ homeostasis dysregulation in Alzheimer’s disease: a focus on plasma membrane and cell organelles. FASEB J. 2019;33(6):6697-6712. doi: https://doi.org/10.1096/fj.201801751R
Wang Y, Mattson MP. L-type Ca2+ currents at CA1 synapses, but not CA3 or dentate granule neuron synapses, are increased in 3xTgAD mice in an age-dependent manner. Neurobiol. Aging. 2014;35(1):88-95. doi: https://doi.org/10.1016/j.neurobiolaging.2013.07.007
Woodruff G, Young JE, Martinez FJ, Buen F, Gore A, Kinaga J, Li Z, Yuan SH, Zhang K, Goldstein LS. The presenilin-1 ΔE9 mutation results in reduced γ-secretase activity, but not total loss of PS1 function, in isogenic human stem cells. Cell Rep. 2013;5(4):974-985. doi: https://doi.org/10.1016/j.celrep.2013.10.018
Zamponi GW, Striessnig J, Koschak A, Dolphin AC. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol. Rev. 2015;67(4):821-870. doi: https://doi.org/10.1124/pr.114.009654
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 172, No. 12, pp. 792-796, December, 2021
Rights and permissions
About this article
Cite this article
Skobeleva, K.V., Ryazantseva, М.A. & Kaznacheyeva, Е.V. Increased Calcium Influx through L-Type Calcium Channels in Hippocampal Neurons with Exogenous Expression of Presenilin-1 ΔE9 Mutant. Bull Exp Biol Med 172, 785–788 (2022). https://doi.org/10.1007/s10517-022-05478-3
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10517-022-05478-3