Interaction of deoxycholate with the sodium channel of squid axon membranes.

Abstract

A B S T R A C T Deoxycholate can react with sodium channels with a high potency. The apparent dissociation constant for the saturable binding reaction is 2/zM at 8~ and the heat of reaction is ~-7 kcal/mol. Four independent tests with Na-free media, K-free media, tetrodotoxin, and pancuronium unequivocally indicate that it is the sodium channel that is affected by deoxyeholate. Upon depolarization of the membrane, the drug modified channel exhibits a slowly activating and noninactivating sodium conductance. The kinetic pattern of the modified channel was studied by increasing deoxycholate concentration, lowering the temperature, chemical elimination of sodium inactivation, or conditioning depolarization. The slow activation of the modified channel can be represented by a single exponential function with the time constant of 1-5 ms. The modified channel is inactivated only partially with a time constant of 1 s. The reversal potential is unchanged by the drug. Observations in tail currents and the voltage dependence of activation suggest that the activation gate is actually unaffected. The apparently slow activation may reflect an interaction between deoxycholate and the sodium channel in resting state.

Irreversible modification of sodium channel inactivation in toad myelinated nerve fibres by the oxidant chloramine‐T.

“…Maintained sodium currents, also referred to as non-inactivating or slowly inactivating sodium currents (see Meves, 1978), have been studied in detail before by using pronase, N-bromoacetamide (Armstrong et al 1973;Oxford et al 1978), scorpion venoms (Gillespie & Meves, 1980) and deoxycholate (Wu, Sides & Narahashi, 1980). From the results presented here it is apparent that the maintained sodium currents caused by chloramine-T treatment have essentially normal activation kinetics.…”

“…From the results presented here it is apparent that the maintained sodium currents caused by chloramine-T treatment have essentially normal activation kinetics. The maintained currents are therefore unlikely to arise from a class of slowly opening sodium channels or by reopening of the inactivated sodium channels, as suggested for the maintained currents observed under treatment with deoxycholate (Wu et al 1980) or scorpion venom (Gillespie & Meves, 1980). It is more likely that the maintained currents are due to removal of the inactivation process, i.e.…”

Extracellular pancuronium affects sodium current in chick embryo sensory neurones

“…According to this view, pancuronium, permeating the DRG cell membrane, may in part reach its binding site through the hydrophobic pathway before the Na' channel opening. The channel activation, therefore, might be apparently delayed by the rate-limiting process of drug dissociation, as observed for lipophific steroids like deoxycholate (Wu et al, 1980). Interestingly, the observed residual outward current is also affected by pancuronium.…”

Effects of 4-aminopyridine on the action potential and the after-hyper polarization of cat spinal motoneurons

“…This has been found in cockroach mons (Pelhate and Pichon 1974), frog motoneurons (Arenssn and Nistri 1985), rat hippocampal slices (Buckle and Haas 1982), and guinea-pig cortex (Galvan et al 1982). Voltage clamp studies indicate that 4-AP is a highly selective blocker of K current in squid giant axon (Yeh et ale 1976), presynaptic fibres of squid synapses (Llinas et al 1976), frog myelinated nerve (Ulbricht and Wagner 1976), and lobster axon (Wu et al 1980). In addition, it has been reported that the transient A current, also mediated by K+ , is blocked by 4-AP in the rat locus coeruleus and in molluscan central neurons (Williams et al 1984;Thompson 1982 phase of the action potential, while the slower K conductance is responsible for the prolonged after-hyperpolarization (Bmett et al 1980).…”