Calmodulin-binding domains in Alzheimer’s disease proteins: extending the calcium hypothesis

O’Day, Danton H.; Myre, Michael A.

doi:10.1016/j.bbrc.2004.06.070

Cited by 59 publications

(61 citation statements)

References 22 publications

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“…It has been previously reported that Ca 2+ overload can modulate APP metabolism, and accelerate APP hydrolysis to generate more Aβ (Wang et al, 1994; Ye et al, 2010). Our study and others have shown that Ca increases with age in the brain, and provides further evidence supporting the hypothesis of the imbalance of calcium homeostasis and disturbed Ca flux in the brain can enhance AD progression (Peterson et al, 1985, 1989; Deary and Hendrickson, 1986; Martyn et al, 1989; Kelliher et al, 1999; O’Day and Myre, 2004; Attems et al, 2008). …”

Section: Discussionsupporting

confidence: 90%

Identification of Cerebral Metal Ion Imbalance in the Brain of Aging Octodon degus

Braidy

Poljak

Marjo

et al. 2017

Front. Aging Neurosci.

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The accumulation of redox-active transition metals in the brain and metal dyshomeostasis are thought to be associated with the etiology and pathogenesis of several neurodegenerative diseases, and Alzheimer’s disease (AD) in particular. As well, distinct biometal imaging and role of metal uptake transporters are central to understanding AD pathogenesis and aging but remain elusive, due inappropriate detection methods. We therefore hypothesized that Octodon degus develop neuropathological abnormalities in the distribution of redox active biometals, and this effect may be due to alterations in the expression of lysosomal protein, major Fe/Cu transporters, and selected Zn transporters (ZnTs and ZIPs). Herein, we report the distribution profile of biometals in the aged brain of the endemic Chilean rodent O. degus—a natural model to investigate the role of metals on the onset and progression of AD. Using laser ablation inductively coupled plasma mass spectrometry, our quantitative images of biometals (Fe, Ca, Zn, Cu, and Al) appear significantly elevated in the aged O. degus and show an age-dependent rise. The metals Fe, Ca, Zn, and Cu were specifically enriched in the cortex and hippocampus, which are the regions where amyloid plaques, tau phosphorylation and glial alterations are most commonly reported, whilst Al was enriched in the hippocampus alone. Using whole brain extracts, age-related deregulation of metal trafficking pathways was also observed in O. degus. More specifically, we observed impaired lysosomal function, demonstrated by increased cathepsin D protein expression. An age-related reduction in the expression of subunit B2 of V-ATPase, and significant increases in amyloid beta peptide 42 (Aβ42), and the metal transporter ATP13a2 were also observed. Although the protein expression levels of the zinc transporters, ZnT (1,3,4,6, and 7), and ZIP7,8 and ZIP14 increased in the brain of aged O. degus, ZnT10, decreased. Although no significant age-related change was observed for the major iron/copper regulator IRP2, we did find a significant increase in the expression of DMT1, a major transporter of divalent metal species, 5′-aminolevulinate synthase 2 (ALAS2), and the proto-oncogene, FOS. Collectively, our data indicate that transition metals may be enriched with age in the brains of O. degus, and metal dyshomeostasis in specific brain regions is age-related.

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Section: Discussionsupporting

confidence: 90%

Identification of Cerebral Metal Ion Imbalance in the Brain of Aging Octodon degus

Braidy

Poljak

Marjo

et al. 2017

Front. Aging Neurosci.

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“…In addition to the classical "IQ" Ca 2ϩ -independent CaM-binding motif (which binds apocalmodulin), there are now dozens of other motifs on ion channels that have been identified as CaM binding targets, and even more target sequences that have been implicated as contributing to, or influencing, CaM binding (http://calcium. uhnres.utoronto.ca/ctdb/ctdb/home.html) (Bhattacharya et al, 2004;O'Day and Myre, 2004;Yamniuk and Vogel, 2004). Some of these sequences are called Ca 2ϩ -dependent and only bind CaM under its 4 Ca 2ϩ -associated form.…”

Section: Calmodulin Is Responsible For the Calcium-dependent Componenmentioning

confidence: 99%

Facilitation of P2X7 Receptor Currents and Membrane Blebbing via Constitutive and Dynamic Calmodulin Binding

Roger¹,

Pelegrı́n²,

Surprenant³

2008

Journal of Neuroscience

111

110

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The ATP-gated P2X 7 receptor (P2X 7 R) is a highly unusual calcium-permeable cationic channel in that within seconds of its activation, dramatic and reversible cytoskeletal rearrangements with prominent membrane blebbing occurs. Agonist-induced membrane currents at hyperpolarized potentials show pronounced facilitation during the initial 30 -100 s of receptor activation but mechanisms responsible have not been elucidated. We measured facilitation of ATP-gated currents in HEK cells expressing rat P2X 7 R and delineated distinct calcium-dependent and independent processes. The calcium-dependent facilitation was composed of an instantaneous (millisecond time domain) and slowly developing (time constant, 20 s with maximum agonist stimulation) component. Both components were prevented when recording with a highly specific calmodulin (CaM) inhibitory peptide but only the instantaneous component was reduced by expression of the dominant-negative EF-handless CaM mutant. Coimmunoprecipitation assays detected low levels of CaM binding to unstimulated P2X 7 R, and this increased by 50% during 45 s stimulation of the receptor. We identified a novel 1-5-16 Ca 2ϩ -dependent CaM binding motif in the intracellular C terminus of P2X 7 R; mutations in this domain resulted in the absence of calcium-dependent facilitation and binding of CaM to unstimulated or stimulated receptor. Blockade of CaM binding also delayed membrane blebbing by threefold. Our results demonstrate that CaM binds constitutively to closed P2X 7 R channels and dynamically during channel activation to significantly enhance and prolong calcium entry. This is the first example of CaM deregulating, rather than tightly controlling, calcium entry through an ion channel.

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“…As the major cellular Ca 2+ -binding protein, CaM responds to calcium fluxes by binding and regulating the activity of multiple CaMdependent proteins [4]. Some of these CaM-binding proteins (CaMBPs) are involved in fundamental events of calcium-mediated neuronal function, as well as in processes such as learning and memory [5].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, a search for CaMBPs revealed that many of the proteins intimately linked to AD, such as tau or presenilins, may be calmodulin-binding proteins [5]. CaM consists of two homologous domains (Nand C-terminal), and each domain contains two EF-hand Ca 2+ -binding motifs [6,7].…”

Section: Introductionmentioning

confidence: 99%

Altered Calmodulin Degradation and Signaling in Non-Neuronal Cells from Alzheimer’s Disease Patients

Esteras¹,

Muñoz²,

Alquézar³

et al. 2012

CAR

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Calmodulin-binding domains in Alzheimer’s disease proteins: extending the calcium hypothesis

Cited by 59 publications

References 22 publications

Identification of Cerebral Metal Ion Imbalance in the Brain of Aging Octodon degus

Identification of Cerebral Metal Ion Imbalance in the Brain of Aging Octodon degus

Facilitation of P2X7 Receptor Currents and Membrane Blebbing via Constitutive and Dynamic Calmodulin Binding

Altered Calmodulin Degradation and Signaling in Non-Neuronal Cells from Alzheimer’s Disease Patients

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