Abstract
Diverse ligands of the muscle nicotinic acetylcholine receptor (nAChR) are used as muscle relaxants during surgery. Although a plethora of such molecules exists in the market, there is still a need for new drugs with rapid on/off-set, increased selectivity, and so forth. We found that pyrroloiminoquinone alkaloid Makaluvamine G (MG) inhibits several subtypes of nicotinic receptors and ionotropic γ-aminobutiric acid receptors, showing a higher affinity and moderate selectivity toward muscle nAChR. The action of MG on the latter was studied by a combination of electrophysiology, radioligand assay, fluorescent microscopy, and computer modeling. MG reveals a combination of competitive and un-competitive inhibition and caused an increase in the apparent desensitization rate of the murine muscle nAChR. Modeling ion channel kinetics provided evidence for MG binding in both orthosteric and allosteric sites. We also demonstrated that theα1 (G153S) mutant of the receptor, associated with the myasthenic syndrome, is more prone to inhibition by MG. Thus, MG appears to be a perspective hit molecule for the design of allosteric drugs targeting muscle nAChR, especially for treating slow-channel congenital myasthenic syndromes.
Highlights
Nicotinic acetylcholine receptors are ligand-gated ion channels organized as pentameric complexes expressed predominantly on the plasma membrane [1]
We have recently discovered that Makaluvamine G (MG) inhibits murine muscle nicotinic acetylcholine receptor (nAChR) and competes with at the orthosteric binding site of muscle-type nAChR of the Torpedo californica electric organ [14]
MG at 2.5 μM co-applied with acetylcholine to the murine muscle nAChR expressed in Xenopus oocytes reduced the acetylcholine-evoked current differently, depending on the application of 10, 25, 100, or 1000 μM acetylcholine (Figure 2A)
Summary
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels organized as pentameric complexes expressed predominantly on the plasma membrane [1]. Classic muscle relaxants bind at the same site as acetylcholine They either cause uncontrolled muscle nAChR activation followed by the desensitization of the receptor and muscle relaxation (as is the case for depolarizing myorelaxant succinylcholine [4]). There are two therapeutics which are used for such purposes namely quinidine [8,9] and fluoxetine [10] They act as non-competitive blockers of nAChRs, but their binding site has not been yet identified [11,12]. Both molecules were not initially dedicated to slow-channel conditions therapy and have many undesirable side-effects. A more detailed analysis of muscle nAChR inhibition by MG and molecular modeling studies of its binding at the muscle nAChR orthosteric site are the purposes of the current study
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