Rapid retrograde regulation of transmitter release at the NMJ

Ribchester, Richard R.; Slater, Clarke R.

doi:10.1016/j.cophys.2018.06.007

Cited by 6 publications

(7 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2017). The mechanism of feedback upregulation at larval Drosophila NMJs involves a postsynaptic‐to‐presynaptic signalling cascade involving Ca 2+ /calmodulin‐dependent protein kinase II, semaphorins, BMPs, plexin B, Deg/ENaC channels and regulation of α2‐δ subunits of Ca 2+ channels (Ribchester & Slater, 2018; Frank et al . 2020).…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, homeostatic upregulation of release at larval Drosophila NMJs, where glutamate is the excitatory neurotransmitter rather than ACh, occurs over a range of extracellular Ca 2+ concentrations (Frank et al 2006;Newman et al 2017). The mechanism of feedback upregulation at larval Drosophila NMJs involves a postsynaptic-to-presynaptic signalling cascade involving Ca 2+ /calmodulin-dependent protein kinase II, semaphorins, BMPs, plexin B, Deg/ENaC channels and regulation of α2-δ subunits of Ca 2+ channels (Ribchester & Slater, 2018;Frank et al 2020). Direct measurements of K + channel function may help to rule out alternative hypotheses that seek to establish general mechanisms of homeostatic plasticity in representative species of these different phylogenetic classes.…”

Section: Presynaptic Effectsmentioning

confidence: 99%

“…Nevertheless, the data indicate potential utility for cyclohexanol as a molecular tool that might facilitate investigation of the homeostatic mechanisms that acutely or chronically regulate synaptic strength, in health and disease (Harris & Ribchester, 1979;Wood & Slater, 2001;Davis & Müller, 2015;Jones et al 2016;Ribchester & Slater, 2018;Frank et al 2020). Postsynaptic nicotinic antagonists produce acute, reversible up-regulation of evoked ACh release (Wang et al 2016;.…”

Section: Presynaptic Effectsmentioning

confidence: 99%

See 2 more Smart Citations

Antagonistic postsynaptic and presynaptic actions of cyclohexanol on neuromuscular synaptic transmission and function

Dissanayake

Margetiny

Whitmore

et al. 2021

The Journal of Physiology

View full text Add to dashboard Cite

Intentional ingestion of agricultural organophosphorus insecticides is a significant public health issue in rural Asia, causing thousands of deaths annually. Some survivors develop a severe, acute or delayed myasthenic syndrome. In animal models, similar myasthenia has been associated with increasing plasma concentration of one insecticide solvent metabolite, cyclohexanol. We investigated possible mechanisms using voltage and current recordings from mouse neuromuscular junctions (NMJs) and transfected human cell lines. Cyclohexanol (10–25 mM) reduced endplate potential (EPP) amplitudes by 10–40% and enhanced depression during repetitive (2–20 Hz) stimulation by up to 60%. EPP decay was prolonged more than twofold. Miniature EPPs were attenuated by more than 50%. Cyclohexanol inhibited whole‐cell currents recorded from CN21 cells expressing human postjunctional acetylcholine receptors (hnAChR) with an IC50 of 3.74 mM. Cyclohexanol (10–20 mM) also caused prolonged episodes of reduced‐current, multi‐channel bursting in outside‐out patch recordings from hnAChRs expressed in transfected HEK293T cells, reducing charge transfer by more than 50%. Molecular modelling indicated cyclohexanol binding (−6 kcal/mol) to a previously identified alcohol binding site on nicotinic AChR α‐subunits. Cyclohexanol also increased quantal content of evoked transmitter release by ∼50%. In perineurial recordings, cyclohexanol selectively inhibited presynaptic K+ currents. Modelling indicated cyclohexanol binding (−3.8 kcal/mol) to voltage‐sensitive K+ channels at the same site as tetraethylammonium (TEA). TEA (10 mM) blocked K+ channels more effectively than cyclohexanol but EPPs were more prolonged in 20 mM cyclohexanol. The results explain the pattern of neuromuscular dysfunction following ingestion of organophosphorus insecticides containing cyclohexanol precursors and suggest that cyclohexanol may facilitate investigation of mechanisms regulating synaptic strength at NMJs. Key points Intentional ingestion of agricultural organophosphorus insecticides is a significant public health issue in rural Asia, causing thousands of deaths annually. Survivors may develop a severe myasthenic syndrome or paralysis, associated with increased plasma levels of cyclohexanol, an insecticide solvent metabolite. Analysis of synaptic transmission at neuromuscular junctions in isolated mouse skeletal muscle, using isometric tension recording and microelectrode recording of endplate voltages and currents, showed that cyclohexanol reduced postsynaptic sensitivity to acetylcholine neurotransmitter (reduced quantal size) while simultaneously enhancing evoked transmitter release (increased quantal content). Patch recording from transfected cell lines, together with molecular modelling, indicated that cyclohexanol causes selective, allosteric antagonism of postsynaptic nicotinic acetylcholine receptors and block of presynaptic K+‐channel function. The data provide insight into the cellular and molecular mechanisms of neuromuscular weakness following int...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Presynaptic Effectsmentioning

confidence: 99%

Section: Presynaptic Effectsmentioning

confidence: 99%

See 1 more Smart Citation

Antagonistic postsynaptic and presynaptic actions of cyclohexanol on neuromuscular synaptic transmission and function

Dissanayake

Margetiny

Whitmore

et al. 2021

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…However, it is unclear which functional receptor state is responsible for nAChR dysfunction and at what phase the depolarization of muscle membranes is interrupted. It has been reported 115 that transmitter release from presynaptic terminals is increased when the downstream nAChRs are blocked. This mechanism could be interpreted as a result of self‐regulation 115 .…”

Section: Treatmentmentioning

confidence: 99%

“…It has been reported 115 that transmitter release from presynaptic terminals is increased when the downstream nAChRs are blocked. This mechanism could be interpreted as a result of self‐regulation 115 . Principally, two hypotheses for dysfunctional neuromuscular transmission are under discussion: a depolarization block of muscle membranes caused by continuous activation of nAChRs, or inhibition of nAChRs due to receptor desensitization.…”

Section: Treatmentmentioning

confidence: 99%

Diagnostics and treatment of nerve agent poisoning—current status and future developments

Amend¹,

Niessen²,

Seeger³

et al. 2020

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

Although 193 states have committed to the Chemical Weapons Convention and 98% of the declared chemical weapons stockpiles have been destroyed so far, nerve agent poisoning remains a lingering threat. The recent dissemination of sarin in Syria, the assassination of Kim Jong-Nam in Malaysia, and the assault on Sergei Skripal in the United Kingdom underline the need for effective treatment. The current therapeutic options of a muscarinic receptor antagonist, an oxime, and an anticonvulsant have been unchanged for decades. Therefore, new therapeutic strategies, for example, bioscavengers and receptor-active substances, are promising concepts that have to be examined for their benefits and limitations. In order to facilitate rapid diagnosis in challenging clinical situations, point-of-care diagnostics and detection are of importance. Therapeutic guidance concerning the duration and success of the current oxime therapy via determination of the cholinesterase status can contribute to an optimal use of resources. In summary, the challenges of current and future therapies for nerve agent poisoning and key diagnostic devices will be discussed.

show abstract

Homeostatic plasticity—a presynaptic perspective

Delvendahl

Müller

2019

Current Opinion in Neurobiology

View full text Add to dashboard Cite

Rapid retrograde regulation of transmitter release at the NMJ

Cited by 6 publications

References 44 publications

Antagonistic postsynaptic and presynaptic actions of cyclohexanol on neuromuscular synaptic transmission and function

Antagonistic postsynaptic and presynaptic actions of cyclohexanol on neuromuscular synaptic transmission and function

Diagnostics and treatment of nerve agent poisoning—current status and future developments

Homeostatic plasticity—a presynaptic perspective

Contact Info

Product

Resources

About