Acetylcholine receptor channels, blocker

All local anaesthetics have some neuromuscular blocking activity and may enhance the block produced by competitive neuromuscular blockers if given in sufficient doses. Procainamide also has acetylcholine receptor channel blocking activity. ... 

A series of potent alkaloids were first isolated from den-drobatid frogs of western Colombia and northwestern Ecuador, but are now known to be more widespread in distribution. These alkaloids affect at least three classes of channels in nerve and muscle. The first two are receptor-regulated channels, in particular the nicotinic acetylcholine receptor channel. The histrionicotoxins are noncompetitive blockers of this receptor-channel complex (Daly et al, 1993). The second class of channels are the voltage-dependent sodium channels. Histrionicotoxins reduce conductances in a manner reminiscent of local anesthetics (Daly et al., 1993). Despite these effects, these alkaloids have relatively low toxicity (Daly et al., 1993). 

Another possibility is that the antagonist interferes with other post-receptor events that contribute to the tissue response. For example, calcium channel blockers such as verapamil block the influx of calcium necessary for maintained smooth muscle contraction hence, they reduce the contractile response to acetylcholine. Some pharmacologists prefer to describe this as a variant of functional antagonism (see above). 

Nakanishi studied philanthotoxin (polyamine-amide) interaction with nicotinic acetylcholine ion-channel [58]. Philanthotoxin-133 (PhTX-133) is a noncompetitive channel-blocker found in venom of the wasp Philanthus. Nicotinic acetylcholine ion-channel is composed of five transmembrane subunits (a, o, P, y, and S), which forms a 270-kDa glycoprotein. The major acetylcholine binding sites are in the a,ex subunits. A 43-kDa cytoplasmic protein is associated non-covalently with the receptor, but interaction with the receptor is not essential for the channel opening (Fig. 6). 

The EOs reduced the contraction induced by acetylcholine, histamine [226-228, 210, 225, 232, 233], carbachol (muscarinic receptor activator) [237] and 5-hydroxytryptamine [229]. The EOs were found to relax intestinal smooth muscle by reducing the influx of Ca [227, 234], K+ [210, 224-226, 229, 230] and Ba [229, 237]. However, other reports have shown that lavender and geranium EOs were unlikely to act as cationic channel blockers [232]. The activities of the EOs resembled those of dicyclomine and atropine (muscarinic receptor antagonists) and dihydropyridine (calcium antagonist) by producing smooth-muscle relaxation [225, 236]. 

Buisson B. and Bertrand D. (1998). Open-channel blockers at the human a4/32 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 53 555-563. 

Several studies employing oocytes of the clawed frog, Xenopus laevis, for the in vitro translation of sodium channel encoding mRNAs (53-55) suggest that this experimental system may be particularly useful toward this end. The biophysical properties of sodium channels expressed in oocytes following injection of rat brain mRNA were similar to those of sodium channels in their native membrane environment, and were specifically inhibited by the sodium channel blockers tetrodotoxin and saxitoxin (i5.). Sodium channels encoded by mRNAs from rat skeletal muscle and eel electroplax have also been expressed in Xenopus oocytes (56-57). To date the expression of insect sodium channels in the Xenopus oocyte has not been reported, but the utility of this system for the translation and expression of insect acetylcholine receptor mRNA has recently been demonstrated (58). Successful application of this methodology to the expression of insect mRNAs encoding functional sodium channels offers a novel method to test some of the hypotheses for the molecular basis of the kdr mechanism. 

Anew 6-Cys/4-loop framework (CC—C—-C—C—C) has been reported for three peptides conotoxins pPnIVAand pPnlVB from C pennaceus (Fainzilber et al., 1994) and aA-conotoxin PIVA of Conus purpurascens (Hopkins et al., 1995). pPnlVA and pPnIVB are sodium channel blockers selective for molluscan neurons they have no effect on sodium currents in bovine chromaffin cells and rat brain synaptosomes (Fainzilber et al., 1994). aA-Conotoxin PIVA is an acetylcholine receptor inhibitor. 

Peptides belonging to the same pharmacological class may have different structural frameworks. Indeed, acetylcholine receptor inhibitors may have the Cys/loop framework CC—C—C of a-conotoxins, CC—C—C—C—C of aA-conotoxins or CC—-C— C—C of a-conotoxin SII. The known sodium channel blockers also have three types of structural framework CC— C—C—-CC (p-conotoxins), C—C—CC—C—-C (conotoxin-GS, pO-conotoxins MrVIA and MrVIB) or CC—C—C—C—-C (p-conotoxins PnIVAand PnIVB). 

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