Effect of polyamines on the nicotinic ACh receptor

Abstract

Introduction. In recent years, interactions of various polyamines with a number of ionotropic receptors have been reported. Such interactions can be either negative (inhibition) or positive (potentiation). It is proposed that hydrophilic polyamines act as open-channel blockers and bind sites deeply in the ion channel pore. Hydrophobic polyamines are believed to act in the shallower part of the pore. There has been cause to think that polyamines with two aromatic moieties block the nicotinic acetylcholine (nACh) receptor by adopting a U-shaped conformation, that is, a conformation in which the long positively charged polyamine chain enters the ion channel while aromatic moieties interact with extracellular parts of α-subunits. Objective. Our goal was to determine whether and how changes in the structure of methoctramine (a polyamine with two aromatic moieties) affect the way in which the nACh receptor is blocked. We synthesized derivatives of methoctramine which have a less flexible structure than methoctramine itself and may be less capable of adopting a U-shaped conformation within the ion channel. Materials and method. Whole-cell ACh-induced currents were recorded from mouse i28 satellite cells expanded in culture. Recordings were performed both in the presence and in the absence of polyamines. Results. All tested polyamines applied at a concentration of 5 mM blocked ACh-induced currents. Depending on the number of protonated nitrogen atoms, polyamines decreased the current amplitude and/or increased the decay rate of the current. Conclusions. We propose two possible mechanisms to explain the action of polyamines: desensitization, and displacement of agonist molecules from their binding sites. The impact of the number of protonated nitrogen atoms is discussed.

Structure and biological action of analogs and derivatives of biogenic polyamines

“…Токсин PhTX-433 47, который содержится в яде ос вида Philanthus triangulum, является сильным антагонистом AMPA и каинатного рецептора [115]. Также отмечено его сильное блокирующее действие на никотиновые ацетилхолиновые рецепторы (nACh) [116]. Наличие активности в отношении iGlu рецепторов, позволило использовать PhTX-433 для определения их субъединичного состава [117].…”