The overexpression of presenilin2 and Alzheimer's-disease-linked presenilin2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells

Lessard, Christian; Lussier, Marc; Cayouette, Sylvie; Bourque, Geneviève; Boulay, Guylain

doi:10.1016/j.cellsig.2004.09.005

Cited by 68 publications

(52 citation statements)

References 57 publications

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“…We also found that Rya-r44F 10559 suppressed both phenotypes, and pain EP2621 suppressed Psn-dependent notum phenotypes (Table 1). Since Rya-r44F and pain encode homologs of known Psn-interactors in vertebrates (Chan et al, 2000;Lessard et al, 2005;Rybalchenko et al, 2008b), this further supports our observed genetic interactions and provides strong evidence that Presenilin function is associated with intracellular calcium sensing and release.…”

Section: Characterization Of Psn Modifierssupporting

confidence: 85%

“…The pain gene encodes an ion channel in the transient receptor potential (TRP) family, and is involved in sensing mechanical and thermal stimuli (Tracey et al, 2003). Presenilin has been shown to influence the calcium signaling activity of another member of the TRP family, known as TRPC6, in human embryonic kidney cells (Lessard et al, 2005). RdgB is an integral membrane phosphatidylinositol transfer protein that is involved in photoreceptor development and regulating the light response, and may function as a calcium transporter (Paetkau et al, 1999;Vihtelic et al, 1991 …”

Section: Characterization Of Psn Modifiersmentioning

confidence: 99%

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Identifying genes that interact with Drosophila presenilin and amyloid precursor protein

Hoef

Hughes

Livne‐Bar

et al. 2009

Genesis

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The gamma-secretase complex is involved in cleaving transmembrane proteins such as Notch and one of the genes targeted in Alzheimer's disease known as amyloid precursor protein (APP). Presenilins function within the catalytic core of gamma-secretase, and mutated forms of presenilins were identified as causative factors in familial Alzheimer's disease. Recent studies show that in addition to Notch and APP, numerous signal transduction pathways are modulated by presenilins, including intracellular calcium signaling. Thus, presenilins appear to have diverse roles. To further understand presenilin function, we searched for Presenilin-interacting genes in Drosophila by performing a genetic modifier screen for enhancers and suppressors of Presenilin-dependent Notch-related phenotypes. We identified 177 modifiers, including known members of the Notch pathway and genes involved in intracellular calcium homeostasis. We further demonstrate that 53 of these modifiers genetically interacted with APP. Characterization of these genes may provide valuable insights into Presenilin function in development and disease.

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Section: Characterization Of Psn Modifierssupporting

confidence: 85%

Section: Characterization Of Psn Modifiersmentioning

confidence: 99%

Identifying genes that interact with Drosophila presenilin and amyloid precursor protein

Hoef

Hughes

Livne‐Bar

et al. 2009

Genesis

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“…In order to obtain a better estimate of basal Ca 2+ influx in these experiments, the cells were first perfused with Ca 2+ in the absence of OAG and then re-perfused with Ca 2+ in the presence of OAG (Fig. 11) reported that over-expression of TRPC6 in either COS (Boulay et al 1997;Zhang & Saffen, 2001), CHO (Hofmann et al 1999) or HEK 293 cells (Lessard et al 2005) is associated with an increase in Ca 2+ influx in response to receptor stimulation and OAG. In contrast, increasing extracellular Ca 2+ concentration in Na + -containing buffers during the recording of TRPC6 currents by voltage-clamp technique caused a reduction in both inward and outward current, suggestive of channel blockade (Inoue et al 2001;Shi et al 2004).…”

Section: Effect Of Membrane Potentialmentioning

confidence: 99%

Human TRPC6 expressed in HEK 293 cells forms non‐selective cation channels with limited Ca²⁺ permeability

Estacion

Sinkins

Jones

et al. 2006

The Journal of Physiology

111

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TRPC6 is thought to be a Ca2+ -permeable cation channel activated following stimulation of G-protein-coupled membrane receptors linked to phospholipase C (PLC). TRPC6 current is also activated by exogenous application of 1-oleoyl-acetyl-sn-glycerol (OAG) or by inhibiting 1,2-diacylglycerol (DAG) lipase activity using RHC80267. In the present study, both OAG and RHC80267 increased whole-cell TRPC6 current in cells from a human embryonic kidney cell line ( pore-permeation model in which Ca2+ acts primarily as a blocking ion and contributes only a small percentage (∼4%) to whole-cell currents in the presence of extracellular Na + . Measurement of single-cell fura-2 fluorescence during perforated-patch recording of TRPC6 currents showed that OAG increased [Ca 2+ ] i 50-100 nM when the membrane potential was clamped at between −50 and −80 mV, but had little or no effect if the membrane potential was left uncontrolled. These results suggest that in cells exhibiting a high input resistance, the primary effect of activating TRPC6 will be membrane depolarization. However, in cells able to maintain a hyperpolarized potential (e.g. cells with a large inwardly rectifying or Ca 2+ -activated K + current), activation of TRPC6 will lead to a sustained increase in [Ca 2+ ] i . Thus, the contribution of TRPC6 current to both the kinetics and magnitude of the Ca 2+ response will be cell specific and dependent upon the complement of other channel types.

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“…Mutations in the presenilin genes are linked to the development of early-onset Alzheimer's and transient expression of presenilin mutants (N141I, M239V) along with TRPC6 in human embryonic kidney -293 cells results in a strong inhibition of agonist (1-oleoyl-2-acetyl-sn-glycerol (OAG) and angiotensin II (Ang II)) induced Ca 2+ entry. Interestingly, the loss of function PS mutant D263A augments the activity of TRPC6 [328,329].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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The overexpression of presenilin2 and Alzheimer's-disease-linked presenilin2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells

Cited by 68 publications

References 57 publications

Identifying genes that interact with Drosophila presenilin and amyloid precursor protein

Identifying genes that interact with Drosophila presenilin and amyloid precursor protein

Human TRPC6 expressed in HEK 293 cells forms non‐selective cation channels with limited Ca²⁺ permeability

Ion Channels as Drug Targets in Central Nervous System Disorders

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The overexpression of presenilin2 and Alzheimer's-disease-linked presenilin2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells

Cited by 68 publications

References 57 publications

Identifying genes that interact with Drosophila presenilin and amyloid precursor protein

Identifying genes that interact with Drosophila presenilin and amyloid precursor protein

Human TRPC6 expressed in HEK 293 cells forms non‐selective cation channels with limited Ca2+ permeability

Ion Channels as Drug Targets in Central Nervous System Disorders

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Human TRPC6 expressed in HEK 293 cells forms non‐selective cation channels with limited Ca²⁺ permeability