The selective action of quinacrine on high‐threshold calcium channels in rat hippocampal cells

Abstract

1 The whole-cell patch-clamp technique has been used to examine Ca channel currents carried by Ba (IBa) in rat hippocampal neurones.2 Quinacrine selectivity decreased the high-threshold current activated by membrane depolarization from a holding potential of -70 mV. Neither the low-threshold Ca channel current nor the fast tetrodotoxin (TTX)-sensitive sodium current were affected by quinacrine.3 Bath application of quinacrine caused a dose-dependent reduction of the peak amplitude of IBa. This effect was fast, voltage-independent, reversible and had a Kd of 30 ± 5 fAM. 4 The quinacrine-induced block did not change the time-course and the voltage dependence of IBa activation and deactivation. The inhibition revealed no use-dependence, ruling out an open channel block by quinacrine. 5 p-Bromophenacyl bromide had no effect on 'Ba suggesting the lack of involvement of phospholipase A2 in the action of quinacrine. In addition, the quinacrine-induced block was not related to the calmodulin pathway and internal quinacrine did not affect the peak amplitude of IBa.6 The effect of quinacrine on the amplitude of hBa was dependent of the external pH, and suggested that only the single-protonated form of the drug can bind to the channel receptor with a Kd of 3 EM. Quinacrine and other substituted acridines can thus be useful for pharmacological and structure-activity studies of Ca channels.

Effects of phospholipase A2 inhibitors on coupling of α2‐adrenoceptors to inwardly rectifying potassium currents in guinea‐pig submucosal neurones

“…Figure la,b). These results are in keeping with previous studies which have demonstrated that quinacrine blocks nicotinic currents (Adams & Feltz, 1980), fast transient outward potassium currents (Kehl, 1991), calcium currents (Mironov & Lux, 1992;Sargent et al, 1992) and calcium and creep currents in isolated atrial myocytes (Bielfeld et al, 1986;Yang & Vassalle, 1989). In the present study, quinacrine and 4-BPB also blocked the inward rectification present in the voltage/current curves recorded in control solution (Figure 4), in a manner analogous to the blockade of the inwardly rectifying potassium channels by rubidium or barium (Surprenant & North, 1988).…”

“…In addition to its action as a phospholipase inhibitor, quinacrine has been shown to block ion channels and nicotinic ACh receptors (Adams & Feltz, 1980;Kehl, 1991;Mironov & Lux, 1992). We further examined the effects of quinacrine on nicotinic synaptic and ionophoretic potentials and on directly evoked action potentials.…”

Influence of some phospholipase A2and cytochrome P450 inhibitors on rat arterial smooth muscle K+currents

“…In addition, other currents have been reported to be inhibited by quinacrine. In neurones of the rat hippocampus (Mironov and Lux 1992), in ventricular myocytes of the rat (Stokke et al 1992) and guinea pig (Nagano et al 1996), and in smooth muscle cells from the guinea pig urinary bladder and vas deferens (Nagano et al 1996), an inhibitory influence of this substance on voltageactivated calcium channels has been shown. In addition, the inward rectifying K + conductance of guinea pig submucosal neurones (Evans and Surprenant 1993) and the endogenous glibenclamide-sensitive K + channel of Xenopus oocytes (Sakuta and Yoneda 1994) are inhibited by quinacrine.…”

Mepacrine‐induced inhibition of the inward current mediated by 5‐HT3 receptors in rat nodose ganglion neurones

“…At this concentration-range, mepacrine inhibited acetylcholine bindings to muscarinic (O'Donnell & Howlett, 1991) and nicotinic receptors (Grunhagen & Changeux, 1976;Cox et al, 1985), decreased voltage-gated Ca2+ currents (Mironov & Lux, 1992;Sargent et al, 1992) and a fast transient outward K+ current (Kehl, 1991), depressed Na+/Ca2" and Na+/H' exchange (Shepherd et al, 1991;Karmazyn et at., 1990) and had a cardioprotective effect against ischaemia (Chiariello et al, 1987;Sargent et al, 1992). All these mepacrine effects were independent of phospholipase A2 activity, although the effective mepacrine concentration for the inhibition of phospholipase A2 is also in this range (Billah et al, 1981).…”

“…It binds to DNA (Darzynkiewicz et al, 1984), increases the pH of lysosomes (DiCerbo et al, 1984), competes with the binding of acetylcholine to muscarinic and nicotinic receptors (O'Donnell & Howlett, 1991;Grunhagen & Changeux, 1976;Cox et al, 1985) and may have local anaesthetic-like actions (Grunhagen & Changeux, 1976). Several studies have shown that mepacrine interacts with voltage-gated ion channels such as the fast transient outward K+ channels in rat melanotrophs (Kehl, 1991) and the high-threshold Ca2+ channel in rat hippocampal cells (Mironov & Lux, 1992). Mepacrine has also been reported to inhibit Na+/H' exchange (Karmazyn et al, 1990), Na+/Ca2+ exchange (Shepherd et al, 1991) and to protect animals from myocardial ischaemia (Chariello et al, 1987;Sargent et al, 1992).…”