Actions of the histrionicotoxins at the ion channel of the nicotinic acetylcholine receptor and at the voltage-sensitive ion channels of muscle membranes

• Published in: Molecular pharmacology Vol. 21; no. 2; pp. 351 - 361
• Main Authors: Spivak, C E, Maleque, M A, Oliveira, A C, Masukawa, L M, Tokuyama, T, Daly, J W, Albuquerque, E X
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.03.1982
• Subjects: acetylcholine; Action Potentials - drug effects; Amphibian Venoms - pharmacology; Animals; histrionicotoxins; In Vitro Techniques; Ion Channels - drug effects; Ion Channels - metabolism; Membranes - metabolism; Motor Endplate - drug effects; Muscles - drug effects; Muscles - metabolism; Neuromuscular Junction - drug effects; neuromuscular junctions; potassium; Rana; Rana pipiens; Receptors, Cholinergic - drug effects; Receptors, Nicotinic - drug effects; sodium; Synaptic Transmission - drug effects
• ISSN: 0026-895X; 1521-0111

Various histrionicotoxins tested on frog nerve-muscle preparations showed a qualitative family resemblance to one another. They blocked the nerve-evoked muscle twitch and depressed both the peak amplitudes and the decay time constants of end-plate currents. During repetitive stimulation they progressively decreased the rate of rise and prolonged the falling phase of muscle action potentials, the latter resulting, at least in part, from blockade of voltage-sensitive potassium channels. These results indicated that the histrionicotoxins act at three membrane channels: the channel associated with the acetylcholine receptor, the sodium channel, and the potassium channel. Closer study of perhydrohistrionicotoxin suggested either two topographically distinct sites of action at the acetylcholine receptor-ion channel complex, or one site and two ion channel complex conformations. One site or conformation only alters the kinetics of channel closure. As these sites become saturated, the end-plate current decay time constant asymptotically approaches a limiting value. The other site or conformation prevents the channel from opening altogether. Further analysis indicated that the binding site for perhydrohistrionicotoxin that alters the kinetics of channel closure has an affinity constant of 0.1 microM-1 at -90 mV and that this affinity may be sensitive to the membrane potential. The lipid protein interface is a suggested site of histrionicotoxin action, common to the three channels studied here as well as to other intrinsic membrane proteins affected by histrionicotoxins.