Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848283 (rundown)
 502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a newly synthesized series of DMAE analogues (bis-diethyl analogue of hemicholinium-3), selected chemicals (TL-402 = NAM-242 greater than JGC-VII-110) showed significant protection of mouse lethality after acute toxic doses of paraoxon (in vivo). DMAE and NAM-250 (like hemicholinium-3) showed minimal or no antagonism against paraoxon-induced toxicity in mice. Studies with DMAE analogues demonstrate weak anticholinesterase activity. The pattern for the neuromuscular inhibition of TL-402, NAM-242 and JGC-VII-110 is different from that of hemicholinium-3. LD50 studies identified compounds with less inherent toxicity (TL-402, NAM-242 and JGC-VII-110) and showed significant antagonism in contrast to DMAE and NAM-250. These chemicals (DMAE and NAM-250) are as toxic as the parent compound hemicholinium-3. All compounds in this series showed potent antinicotinic activity in different nicotinic-receptor preparations. The antinicotinic activity correlates with their action on the acetylcholine receptor-ion channel complex at frog neuromuscular junctions (in vitro). Electrophysiological studies demonstrate that the antinicotinic agents significantly depressed both the end plate current (EPC) amplitude and the time constant of decay (tau EPC) at the end plate of frog. In presence of paraoxon, voltage- and concentration-dependent shortening of tau EPC is observed which is more prominent than the decrease of the amplitude of EPC. The antinicotinic agents which showed significant antagonism of paraoxon both in vivo and in vitro (TL-402, NAM-242 and JGC-VII-110) also produced profound tetanic rundown after neurally or ionophoretically evoked EPC. These effects are voltage-dependent. The marked shortening of tau EPC, linear relationship between 1/tau vs DMAE analogue concentrations and potential-dependent tetanic rundown suggest that these analogues produce antagonism of paraoxon primarily by reducing end plate permeability by blocking nicotinic ACh-R associated ion channels in their open form. The antinicotinic activity of these agents is related to acetal or corresponding ether substitution.
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PMID:Mechanism for antagonism of paraoxon by hemicholinium-3 analogues. 196 41

Although sodium-activated potassium channels (KNa) have been suggested to shape various firing patterns in neurons, including action potential repolarization, their requirement for high concentrations of Na+ to gate conflicts with this view. We characterized KNa channels in adult rat dorsal root ganglion (DRG) neurons. Using immunohistochemistry, we found ubiquitous expression of the Slack KNa channel subunit in small-, medium-, and large-diameter DRG neurons. Basal KNa channel activity could be recorded from cell-attached patches of acutely dissociated neurons bathed in physiological saline, and yet in excised inside-out membrane patches, the Na+ EC50 for KNa channels was typically high, approximately 50 mM. In some cases, however, KNa channel activity remained considerable after initial patch excision but decreased rapidly over time. Channel activity was restored in patches with high Na+. The channel rundown after initial excision suggested that modulation of channels might be occurring through a diffusible cytoplasmic factor. Sequence analysis indicated that the Slack channel contains a putative nicotinamide adenine dinucleotide (NAD+)-binding site; accordingly, we examined the modulation of native KNa and Slack channels by NAD+. In inside-out-excised neuronal patch recordings, we found a decrease in the Na+ EC50 for KNa channels from approximately 50 to approximately 20 mM when NAD+ was included in the perfusate. NAD+ also potentiated recombinant Slack channel activity. NAD+ modulation may allow KNa channels to operate under physiologically relevant levels of intracellular Na+ and hence provides an explanation as to how KNa channel can control normal neuronal excitability.
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PMID:NAD+ activates KNa channels in dorsal root ganglion neurons. 1938 8