Effects of organophosphorus anticholinesterases on nicotinic receptor ion channels at adult mouse muscle endplates

Tattersall, J.E.H.

doi:10.1111/j.1476-5381.1990.tb12713.x

Cited by 34 publications

(5 citation statements)

References 35 publications

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“…2003; Neher and Steinbach 1978; Spitzmaul et al. 2009; Tattersall 1993), a picture that describes our observations for εV265A‐AChR. For WT channels as well as αV255A‐, βV266A‐, and δV269A‐AChR, there is no effect on the kinetics of channel openings, although channel closures become longer in the presence of verapamil, as if the drug impedes channel opening, but then has no effect on the open‐channel conformation, as shown by the unaltered open times.…”

Section: Discussionsupporting

confidence: 63%

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Mechanism of verapamil action on wild‐type and slow‐channel mutant human muscle acetylcholine receptor

Moriconi

Castro

Fucile

et al. 2010

Journal of Neurochemistry

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Verapamil, a Ca 2+ channel blocker widely used in clinical practice, also affects the properties of frog and mouse muscle acetylcholine receptor (AChR). Here, we examine the mechanism of action of verapamil on human wild-type and slowchannel mutant muscle AChRs harboring in any subunit a valine-to-alanine mutation of 13¢ residue of the pore-lining M2 transmembrane segment. Verapamil, after a pre-treatment of 0.5-10 s, accelerated the decay of whole-cell or macroscopic outside-out currents within milliseconds of ACh application even at clinically attainable doses. Recordings of unitary events in the cell-attached and outside-out configurations showed that verapamil does not alter single-channel conductance, but reduces channel open probability, by prolonging the dwell time into the closed state for wild-type and all mutant AChR. The duration of channel openings decreased only for the eV265A-AChR, by shortening the longest exponential component of the open-time distribution. These results provide a rationale for the therapeutic use of verapamil in the slow-channel syndrome and emphasize the major role played by e subunit in controlling the functional properties of human muscle AChR, as revealed by the peculiar alterations imparted by mutations in this subunit.

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Section: Discussionsupporting

confidence: 63%

“…Single‐channel recordings obtained under outside‐out or cell‐attached conditions were filtered at 5 KHz and sampled at 25 KHz, as in previous studies dealing with AChR blockade (see for instance, Grassi 1999; Tattersall 1993). Data were analyzed as previously described (Di Castro et al.…”

Section: Methodsmentioning

confidence: 99%

Mechanism of verapamil action on wild‐type and slow‐channel mutant human muscle acetylcholine receptor

Moriconi

Castro

Fucile

et al. 2010

Journal of Neurochemistry

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“…The development of desensitization of the nicotinic AChR channel has been demonstrated by the time-dependent decrease in channel opening frequency using patch clamp technique (Dionne, 1989;Tattersall, 1990;Nojima et al, 1994). In the present study, we found that the time-dependent decrease in channel opening frequency of STZ-diabetic muscle cells was greatly accelerated compared with normal cells in 2.5 mM Ca2".…”

Section: Discussionsupporting

confidence: 56%

Accelerated desensitization of nicotinic receptor channels and its dependence on extracellular calcium in isolated skeletal muscles of streptozotocin‐diabetic mice

Nishimura

Tsuneki

Kimura

et al. 1995

British J Pharmacology

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1 To elucidate the influence of the diabetic state on desensitization of nicotinic acetylcholine (ACh) receptor channels, we investigated the time course of the decrease in amplitude of ACh potentials elicited by iontophoretic application to isolated diaphragm muscle of streptozotocin-diabetic mice. We also investigated time-and extracellular Ca2+-dependent changes in the channel opening frequency of AChactivated channel currents and the involvement of protein kinases by use of the cell-attached patch clamp technique in single skeletal muscle cells. 2 When ACh potentials were evoked at 10 Hz, the decline in trains of ACh potentials was accelerated in the diabetic state. 3 The time-dependent decrease in the channel opening frequency of diabetic muscle cells was greatly accelerated compared with normal cells in 2.5 mM Ca2" medium.4 This accelerated decrease in channel opening frequency was restored by pretreatment with a protein kinase C inhibitor, staurosporine (10 nM) but neither a protein kinase A inhibitor, H-89 (3 gM) nor a calmodulin kinase II inhibitor, KN-62 (5 gM) were able to restore the fall in opening frequency.5 These results demonstrate that in the diabetic state the desensitization of nicotinic ACh receptor channels may be greatly accelerated by activating protein kinase C, which is caused by an increase in the amount of available intracellular Ca2 .

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“…Interestingly, nAChR blockade enhanced DFP-mediated PS1 inhibition in both the dH and the vH. Prior evidence indicates that acute OP exposure accelerates the rate of nAChR desensitization (Tattersall, 1990), an effect that may contribute to the enhanced PS1 inhibition observed in the present study. Specifically, this enhanced inhibition may be a result of reducing the excitatory tone of α7like nAChRs located on stratum pyramidale principal cells (Castro and Albuquerque, 1993;Mike JPET # 263053 et al, 2000).…”

Section: Jpet # 263053supporting

confidence: 65%

Dorsoventral-Specific Effects of Nerve Agent Surrogate Diisopropylfluorophosphate on Synaptic Transmission in the Mouse Hippocampus

Brown

Filipov

Wagner

2020

J Pharmacol Exp Ther

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Diisopropylfluorophosphate (DFP) is a common surrogate for nerve agents used in rodent models of Gulf War Illness (GWI) and is known to alter hippocampal synaptic transmission. Although there has been an increased appreciation for functional differences in the hippocampus between the dorsal (dH) and ventral (vH) sectors, there is a paucity of comparative information characterizing the effects of GWI‐relevant chemicals in the dH and the vH. Our objective was to investigate the effects of acute DFP exposure on hippocampal synaptic transmission using extracellular recording from mouse dH and vH slice preparations. DFP (30 μM) was washed‐in for 30 min while population spike (PS) amplitude was monitored. PS amplitude in the dH and vH was decreased by DFP. Following pretreatment with the nicotinic antagonist mecamylamine (MEC, 30 μM), the DFP‐induced PS inhibition was enhanced in both the dH and vH. In contrast, pretreatment with the muscarinic antagonist atropine (ATR, 3 μM) resulted in DFP enhancement of the PS amplitude in the dH whereas PS inhibition was still observed in the vH. Coapplication of ATR and MEC prevented DFP‐mediated modulation of PS amplitude in the dH but the cholinergic antagonists had no effect on DFP‐mediated PS inhibition in the vH. Similar to ATR pretreatment experiments, dH slices preexposed to the M2 selective antagonist AFDX‐116 (300 nM) exhibited enhanced PS amplitude whereas AFDX‐116 had no effect in the vH. Regarding possible non‐cholinergic mechanisms, DFP has been shown to directly interact with the NMDA receptor (NMDAR). Combined pretreatment with AFDX‐116, MEC, and the competitive NMDAR antagonist D‐APV (25 μM) prevented all DFP‐induced modulation of the PS in both the dH and vH. The AFDX‐116 blockade of the DFP‐mediated PS inhibition in the dH suggests an M2R‐dependent inhibition of excitation in CA1; however, in the vH this DFP effect is primarily mediated by a non‐cholinergic mechanism. Notably, pretreatment with D‐APV alone prevented a decrease in PS amplitude in the dH and the vH, suggesting a common involvement of NMDARs in DFP actions in both hippocampal sectors. Population spike paired‐pulse ratio (PS PPR) was also monitored to assess the impact of DFP exposure on recurrent inhibition. DH and vH slices exposed to DFP exhibited increased PS PPR, consistent with a reduction in inhibitory influence in CA1. Interestingly, in dH and vH slices pretreated with cholinergic antagonists, we still observed a DFP‐mediated increase of PS PPR whereas D‐APV pretreatment alone prevented this increase. Previous reports have demonstrated impairments in hippocampal‐dependent behavioral performance in both animal models and GWI patient populations. Mechanistic distinctions along the septotemporal axis that underlie the actions of DFP on synaptic activity may have important implications for potential therapeutic approaches to the treatment of GWI. Support or Funding Information Department of Defense (to NMF and JJW [Award: W81XWH‐16‐1‐0586]) and UGA Interdisciplinary Toxicology Program (to KAB) Th...

show abstract

Effects of organophosphorus anticholinesterases on nicotinic receptor ion channels at adult mouse muscle endplates

Cited by 34 publications

References 35 publications

Mechanism of verapamil action on wild‐type and slow‐channel mutant human muscle acetylcholine receptor

Mechanism of verapamil action on wild‐type and slow‐channel mutant human muscle acetylcholine receptor

Accelerated desensitization of nicotinic receptor channels and its dependence on extracellular calcium in isolated skeletal muscles of streptozotocin‐diabetic mice

Dorsoventral-Specific Effects of Nerve Agent Surrogate Diisopropylfluorophosphate on Synaptic Transmission in the Mouse Hippocampus

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