The effects of doxapram (blocker of K2p channels) on resting membrane potential and synaptic transmission at the Drosophila neuromuscular junction

Vacassenno, Rachael M.; Haddad, Christine N.; Cooper, Robin L.

doi:10.1016/j.cbpc.2022.109497

Cited by 4 publications

(10 citation statements)

References 41 publications

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“…Since the crayfish neuromuscular junction (NMJ) had not been investigated previously for the effect of doxapram, two different concentrations of doxapram were used to examine the outcome. In a previous report, doxapram at 10 mM was needed to block the action of LPS at the larval Drosophila NMJ [ 19 ]. Thus, concentrations of 5 mM and 10 mM were used in this study.…”

Section: Resultsmentioning

confidence: 99%

“…At the larval Drosophila NMJ, doxapram partially blocked the effect of LPS on increasing the heart rate in larval Drosophila [ 29 ]. Doxapram (10 mM) alone depressed the heart rate in larval Drosophila , depolarized the larval body wall muscles, and caused spontaneous firing of the motor neuron producing random EJPs [ 19 ]. However, doxapram at 5 mM or 10 mM did not depolarize the crayfish opener muscle or result in spontaneous EJPs as shown in the investigations herein.…”

Section: Resultsmentioning

confidence: 99%

“…If doxapram blocks ion channels in the axon or presynaptic terminal, it is not surprising that the enhanced response by LPS would be dampened. However, the mechanism by which LPS enhances synaptic transmission was not elucidated in the initial report by Parnas et al [ 28 ] or in later reports [ 11 , 16 , 19 ]. Thus, if LPS from Serratia marcescens is promoting Ca 2+ through presynaptic voltage gated ion channels, then it is possible that LPS and doxapram might be targeting the same site of action.…”

Section: Discussionmentioning

confidence: 99%

“…Doxapram (5 and 10 mM) at the larval Drosophila NMJ rapidly depolarizes the muscle, maintains the muscle in a depolarized state, and causes the motor nerve to fire and produce random evoked EJPs [ 19 ]. Thus, doxapram depolarizes both the muscle and the motor nerve terminal at the larval Drosophila NMJ.…”

Section: Discussionmentioning

confidence: 99%

“…The direct action of LPS on the larval Drosophila heart and neuromuscular junctions is speculated to alter the membrane potential by transiently activating a K + channel subtype known as a K2P (two-P-domain K + subunits) subtype, which helps to maintain the resting membrane potential of the cells [ 2 , 18 ]. The compound, doxapram (trade names, Stimulex or Respiram), blocked the acute actions of LPS from Serratia marcescens [ 11 , 19 ]. Recently, it was demonstrated that LPS from Serratia marcescens also has rapid effects on the NMJs of crayfish but with different effects than those reported for the NMJs of the larval Drosophila .…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

The Effects of Doxapram Blocking the Response of Gram-Negative Bacterial Toxin (LPS) at Glutamatergic Synapses

Brock

Cooper

2023

Biology

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Lipopolysaccharides (LPS) associated with Gram-negative bacteria are one factor responsible for triggering the mammalian immune response. Blocking the action of LPS is key to reducing its downstream effects. However, the direct action of LPS on cells is not yet fully addressed. LPS can have rapid, direct effects on cells in the absence of a systemic immune response. Recent studies have shown that doxapram, a blocker of a subset of K2P channels, also blocks the acute actions of LPS. Doxapram was evaluated to determine if such action also occurs at glutamatergic synapses in which it is known that LPS can increase synaptic transmission. Doxapram at 5 mM first enhanced synaptic transmission, then reduced synaptic response, while 10 mM rapidly blocked transmission. Doxapram at 5 mM blocked the excitatory response induced by LPS. Enhancing synaptic transmission with LPS and then applying LPS combined with doxapram also resulted in retarding the response of LPS. It is possible doxapram and LPS are mediated via a similar receptor or cellular responses. The potential of designing pharmacological compounds with a similar structure to doxapram and determining the binding of such compounds can aid in addressing the acute, direct actions by LPS on cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Effects of Doxapram Blocking the Response of Gram-Negative Bacterial Toxin (LPS) at Glutamatergic Synapses

Brock

Cooper

2023

Biology

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The effects of doxapram and its potential interactions with K2P channels in experimental model preparations

Elliott,

Brock,

Vacassenno

et al. 2024

J Comp Physiol A

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Effect of Doxapram, a K2p Channel Blocker, and pH on Heart Rate: Larval Drosophila Model

Elliott,

Taul,

Abul-Khoudoud

et al. 2023

Applied Biosciences

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Two-P-domain K+ (K2p) channels are responsible for maintaining the resting membrane potential. K2p channels have varied expression in healthy tissue, but they also change in cancerous or diseased states. The correlation and causation as regards the alteration of K2p channel expression are still being investigated. The compound doxapram seems to block K2p channels and depolarize cells. Using Drosophila, the increased expression of the ORK1 K2p channel in cardiac and skeletal muscle was investigated. The heart rate in larval Drosophila is very sensitive to pH, and since doxapram blocks a subset of the K2p channels that are known to be acid-sensitive, it was postulated that doxapram would affect heart rate. A pH change from 7.1 to 6.5 increased the rate, while that from 7.1 to 7.5 decreased the rate. An amount of 0.1 mM of doxapram had no effect, but 0.5 of mM depressed Drosophila heart rates within five minutes. Exposure to 5 mM of doxapram immediately decreased the rate. Lipopolysaccharides (LPSs) from Gram-negative bacteria acutely increased the rate. LPSs activate K2p channels in the skeletal muscle of larvae and are blocked by doxapram. LPSs slightly reduce depression in the rate induced by doxapram. The overexpression of K2p channels in the heart and skeletal muscle depressed the heart rate and heightened pH sensitivity. At larval neuromuscular junctions, the overexpression in skeletal muscle increases the frequency of spontaneous quantal events and produces a more negative resting membrane potential.

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The effects of doxapram (blocker of K2p channels) on resting membrane potential and synaptic transmission at the Drosophila neuromuscular junction

Cited by 4 publications

References 41 publications

The Effects of Doxapram Blocking the Response of Gram-Negative Bacterial Toxin (LPS) at Glutamatergic Synapses

The Effects of Doxapram Blocking the Response of Gram-Negative Bacterial Toxin (LPS) at Glutamatergic Synapses

The effects of doxapram and its potential interactions with K2P channels in experimental model preparations

Effect of Doxapram, a K2p Channel Blocker, and pH on Heart Rate: Larval Drosophila Model

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