Voltage Gated Calcium Channel Activation by Backpropagating Action Potentials Downregulates NMDAR Function

Theis, Anne-Kathrin; Rózsa, Balázs; Katona, Gergely; Schmitz, Dietmar; Johenning, Friedrich W.

doi:10.3389/fncel.2018.00109

Cited by 13 publications

(10 citation statements)

References 59 publications

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“…However, little is known about their localization and whether or not they are present in the head of spines despite some studies reporting one to 20 channels [49]. No significant local effect of VGCCs was found to contribute to synaptic depolarization, and the amplitude of Ca 2+ transients induced by excitatory postsynaptic potential seems to be regulated independent of VGCCs, as discussed in [50].…”

Section: Discussionmentioning

confidence: 99%

Fast calcium transients in dendritic spines driven by extreme statistics

et al. 2019

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Fast calcium transients (<10 ms) remain difficult to analyse in cellular microdomains, yet they can modulate key cellular events such as trafficking, local ATP production by endoplasmic reticulum-mitochondria complex (ER-mitochondria complex), or spontaneous activity in astrocytes. In dendritic spines receiving synaptic inputs, we show here that in the presence of a spine apparatus (SA), which is an extension of the smooth ER, a calcium-induced calcium release (CICR) is triggered at the base of the spine by the fastest calcium ions arriving at a Ryanodyne receptor (RyR). The mechanism relies on the asymmetric distributions of RyRs and sarco/ER calcium-ATPase (SERCA) pumps that we predict using a computational model and further confirm experimentally in culture and slice hippocampal neurons. The present mechanism for which the statistics of the fastest particles arriving at a small target, followed by an amplification, is likely to be generic in molecular transduction across cellular microcompartments, such as thin neuronal processes, astrocytes, endfeets, or protrusions.

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Section: Discussionmentioning

confidence: 99%

Fast calcium transients in dendritic spines driven by extreme statistics

et al. 2019

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“…5F and G) achieved a >80% block. 25,26,50 Residual, PD173212-insensitive (up to 1 μM: Fig. 5H) Ca 2+ currents in our experimental conditions were blocked by Cd2 + (Fig.…”

Section: Selective a 3 Ar Activation Inhibits Ca 2+ Currents In Cultured Rat Dorsal Root Ganglion Neuronsmentioning

confidence: 61%

Adenosine A3 receptor activation inhibits pronociceptive N-type Ca2+ currents and cell excitability in dorsal root ganglion neurons

Coppi

Cherchi

Fusco

et al. 2019

Pain

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Recently, studies have focused on the antihyperalgesic activity of the A 3 adenosine receptor (A 3 AR) in several chronic pain models, but the cellular and molecular basis of this effect is still unknown. Here, we investigated the expression and functional effects of A 3 AR on the excitability of small-to medium-sized, capsaicin-sensitive, dorsal root ganglion (DRG) neurons isolated from 3-to 4-week-old rats. Real-time quantitative polymerase chain reaction experiments and immunofluorescence analysis revealed A 3 AR expression in DRG neurons. Patch-clamp experiments demonstrated that 2 distinct A 3 AR agonists, Cl-IB-MECA and the highly selective MRS5980, inhibited Ca 2+ -activated K + (K Ca ) currents evoked by a voltage-ramp protocol. This effect was dependent on a reduction in Ca 2+ influx via N-type voltage-dependent Ca 2+ channels, as Cl-IB-MECA-induced inhibition was sensitive to the N-type blocker PD173212 but not to the L-type blocker, lacidipine. The endogenous agonist adenosine also reduced N-type Ca 2+ currents, and its effect was inhibited by 56% in the presence of A 3 AR antagonist MRS1523, demonstrating that the majority of adenosine's effect is mediated by this receptor subtype. Current-clamp recordings demonstrated that neuronal firing of rat DRG neurons was also significantly reduced by *

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“…The vesicular ACh transporter, Slc18a3 (VAChT), transports ACh into secretory vesicles for release into the synaptic cleft [30]. Neuronal action potential activates the voltage-gated calcium channel [31], of which Cacna2d2 forms the alpha2/delta2 subunit [32]. The in ux of calcium ions, promotes ACh secretion.…”

Section: Cholinergic Neurotransmission Pathways Were Affected By Sde mentioning

confidence: 99%

Cranial Manipulation Modulates Cholinergic Pathway Gene Expression in an Animal Model of Age-related Cognitive Decline

Anandakrishnan

Tobey

Nguyen

et al. 2020

Preprint

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Age dependent dementia is a devastating disorder afflicting the growing older population around the world. Although pharmacological agents improve symptoms of dementia, age related co-morbidities combined with adverse effects often outweigh their clinical benefits. Therefore, non-pharmacological therapies are being investigated as an alternative. Randomized controlled trials and observational studies have shown promising results for cranial manipulation as a treatment for dementia and other nervous system disorders. In this study we examine the effect of osteopathic cranial manipulative medicine (OCMM) on gene expression, in an animal model for age-related cognitive decline (aged rats). We found that OCMM significantly affected the expression of 36 genes in the neuronal pathway (False Discovery Rate (FDR) < 0.004). The top five neuronal genes with the largest fold-change (Slc5a7, Chat, Slc18a3, Adcy5 and Cacna2d2, >2-fold change, FDR<0.004) are part of the cholinergic neurotransmission mechanism, which is known to affect cognitive function. Slc5a7, the highest overexpressed neuronal gene (3-fold change) encodes a sodium and chloride ion-dependent high-affinity transporter that mediates choline uptake for acetylcholine synthesis in cholinergic neurons. This is the pathway enhanced by the clinically used Alzheimer’s disease drug Donepezil, which selectively inhibits acetylcholinesterase, an enzyme that catalyzes endogenous acetylcholine degradation. In addition, 40% of significant differentially expressed (SDE) genes (FDR<0.004), have been previously implicated in neurological disorders. Overall, SDE genes and their role in central nervous system signaling pathways suggest a connection to previously reported OCMM induced behavioral and biochemical changes in rat models of age-dependent dementia. Further investigation in this direction will provide a better understanding of the molecular mechanisms of OCMM and its potential in clinical applications. With clinical validation, OCMM could represent a much needed low-risk adjunct treatment for age-related dementia including Alzheimer’s disease.

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Voltage Gated Calcium Channel Activation by Backpropagating Action Potentials Downregulates NMDAR Function

Cited by 13 publications

References 59 publications

Fast calcium transients in dendritic spines driven by extreme statistics

Fast calcium transients in dendritic spines driven by extreme statistics

Adenosine A3 receptor activation inhibits pronociceptive N-type Ca2+ currents and cell excitability in dorsal root ganglion neurons

Cranial Manipulation Modulates Cholinergic Pathway Gene Expression in an Animal Model of Age-related Cognitive Decline

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