Presynaptic Receptors in the Neuromuscular Junction

Bowman, W. C.; Prior, Chris; Marshall, Ian

doi:10.1111/j.1749-6632.1990.tb31983.x

Cited by 96 publications

(71 citation statements)

References 73 publications

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“…However, drugs may act in several targets (enzymes, receptors) at skeletal neuromuscular junctions, 34 and indeed, some actions, such as blockade of nerve potassium chanels or activation of presynaptic M 1 receptors, may facilitate neurotransmission at this level. 35 Thus, THA may enhance acetylcholine release besides its AChE inhibitory action. 36 We did not test each of these possibilities to explain the discrepancies between the effects of racemates and enantiomers.…”

Section: Discussionmentioning

confidence: 99%

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

et al. 1999

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Eleven new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active.

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Section: Discussionmentioning

confidence: 99%

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

et al. 1999

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“…Although pancuronium is not effective on the ganglionic type of nicotinic receptor (Kharkevich & Shorr 1986), it can, howAuthor for correspondence: Antonio Carlos Oliveira, Department of Pharmacology, Institute of Biomedical Sciences, University of SBo Paulo; Avenida Lineu Prestes 1524, Cidade Universitaria, 05508-900, SBo Paulo, SP, Brazil (fax +55 011 8187322). ever, block muscarinic receptors (Kharkevich & Shorr 1986) which apparently also reside at the motor nerve terminal (Bowman et al 1990;Wessler 1992). Therefore, the presynaptic effect of pancuronium could also be a conjunction of actions exerted on presynaptic muscarinic receptors and on the beforementioned "muscle-type" nicotinic presynaptic receptors (Tian et al 1994).…”

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confidence: 99%

Mechanisms Underlying the Vecuronium‐Induced Tetanic Fade in the Isolated Rat Muscle

Oliveira

1999

Pharmacology & Toxicology

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Abstract:The cellular mechanisms underlying the effects of vecuronium on the tetanic contraction were studied in vitro with a combination of myographic and electrophysiologic techniques. We used the isolated sciatic nerve extensor digitorum longus muscle preparation of the rat. Indirect twitches were evoked at 0.1 Hz pulses and tetani at 50 Hz pulses. Trains of end-plate potentials were generated at 50 Hz. The electrophysiological variables used in the analysis of the end-plate potentials were: amplitude, tetanic run-down, quantal size and quantal content. The myographic study demonstrated that vecuronium at 0.4 pM caused tetanic fade, but left the twitch unaffected. Regarding electrophysiology, vecuronium (0.4 pM ) decreased the amplitude of end-plate potentials and increased their tetanic run-down. These changes were due to significant reductions in both the quantal content of the end-plate potentials and the quantal size. It is concluded that vecuronium has both pre-and postsynaptic effects at the neuromuscular junction, and that it induces fade of the tetanic contraction via a summation of these effects.The mechanisms underlying the fade of the tetanic contraction induced by two different blockers of neuromuscular transmission, hexamethonium (Gallacci & Oliveira 1990) and pancuronium (Gallacci & Oliveira 1994) have been previously studied in our laboratory. They both affected the tetanic contraction via a conjunction of preand postsynaptic effects. However, these compounds differed in the relative potency of presynaptic effect compared to postsynaptic effect. Thus, in the case of hexamethonium the postsynaptic effect was relatively more prominent than the presynaptic effect while the reverse held true in the case of pancuronium (Gallacci & Oliveira 1990.However, the presynaptic changes caused by hexamethonium and those caused by pancuronium are probably not molecularly identical, because they seem to involve different types of presynaptic receptors. Thus, in the case of hexamethonium, its presynaptic effect is probably the algebraic summation of two opposing mechanisms: one, facilitatory, is exerted via a presynaptic receptor resembling the ganglionic-type nicotinic receptor, and another, inhibitory, is exerted via a presynaptic receptor resembling the muscle-type nicotinic receptor (see Tian et al. 1994, for arguments in favour of the presence of both of these types of receptors in the motor nerve terminal). Although pancuronium is not effective on the ganglionic type of nicotinic receptor (Kharkevich & Shorr 1986), it can, how-

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“…Whereas the NMJ has served as an excellent model to elucidate the process of synapse formation, the cellular and molecular mechanisms by which ACh regulates this process are still unclear; this is in part because the expression of ACh receptor (AChR) subtypes varies over space and time during the development of this synapse. For example, each of the constituent parts of the NMJ (including the MN-derived presynaptic nerve terminal, the muscle-derived postsynaptic apparatus, and the perisynaptic Schwann cell) expresses AChR (12,13). Therefore, in this study, we used genetic techniques to study the cellular mechanism by which ACh regulates formation of the vertebrate NMJ.…”

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confidence: 99%

Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms

Lin²,

Yang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Emerging evidence suggests that the neurotransmitter acetylcholine (ACh) negatively regulates the development of the neuromuscular junction, but it is not clear if ACh exerts its effects exclusively through muscle ACh receptors (AChRs). Here, we used genetic methods to remove AChRs selectively from muscle. Similar to the effects of blocking ACh biosynthesis, eliminating postsynaptic AChRs increased motor axon branching and expanded innervation territory, suggesting that ACh negatively regulates synaptic growth through postsynaptic AChRs. However, in contrast to the effects of blocking ACh biosynthesis, eliminating postsynaptic AChRs in agrin-deficient mice failed to restore deficits in pre- and postsynaptic differentiation, suggesting that ACh negatively regulates synaptic differentiation through nonpostsynaptic receptors. Consistent with this idea, the ACh agonist carbachol inhibited presynaptic specialization of motorneurons in vitro. Together, these data suggest that ACh negatively regulates axon growth and presynaptic specialization at the neuromuscular junction through distinct cellular mechanisms.

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Presynaptic Receptors in the Neuromuscular Junction

Cited by 96 publications

References 73 publications

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

Mechanisms Underlying the Vecuronium‐Induced Tetanic Fade in the Isolated Rat Muscle

Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms

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