Effect of haloperidol on the sarcoplasmic reticulum Ca-dependent adenosine triphosphatase

Abstract

Several effects of the neuroleptic agent haloperidol on the sarcoplasmic reticulum (SR) Ca-dependent adenosine triphosphatase (Ca-ATPase) and Ca transport are described. Haloperidol inhibits the Ca-ATPase activity in the presence of calcimycin. The effect depends on the conditions of preexposure of the membranes to the drug: the inhibition increases with the preincubation time; Ca and Mg protect the enzyme against the effect of the drug. The inhibitory effect of haloperidol decreases upon increasing [Ca2+], at constant [Mg], and disappears at 20 mM [Mg] for any [Ca2+], and at 0.5 mM [Ca2+] for any [Mg2+]. Haloperidol also inhibits phosphorylation of the enzyme by Pi, and ATP-dependent Ca2+ uptake, in both cases with apparent Ki = 0.10-0.15 mM, and increases the rate of Ca efflux from preloaded vesicles in this concentration range. The results suggest that haloperidol interacts with the catalytic site, interfering with the effect of the divalent catalytic cation, but not at other steps of the enzymatic cycle, where Mg2+ and Ca2+ are also activators. They are consistent with a reaction model where haloperidol interacts with the E2 conformers of the enzyme, with lower affinity for the phosphoenzyme than for the dephospho species. The inhibition of Ca uptake by SR vesicles is ascribed to an increased Ca2+ permeability rather than to the inhibition of the Ca-ATPase, which requires higher concentrations of the drug.

Effect of carticaine on the sarcoplasmic reticulum Ca 2+ -dependent adenosine triphosphatase

“…It has been previously reported that several hydrophobic drugs interact with the catalytic site in the E 2 enzyme form, tying up the entry of Pi (De Meis et al 1988;Wolosker et al 1992;Takara and Alonso 1996). The present results support a similar interpretation for the effects of carticaine on the Ca 2+ -ATPase.…”

“…The inhibitory effect of carticaine on the ATPase activity does not depend on the preexposition of the SR membranes to the local anesthetic; preexposition to neither Ca 2+ nor Mg 2+ protects the Ca 2+ -ATPase from the inhibitory action of carticaine, as reported for other hydrophobic agents (Takara and Alonso 1996).…”

“…Several authors reported that Ca 2+ leaks through the ATPase in the absence of its physiological ligands (Shoshan et al 1981;Takara and Alonso 1996;Wolosker et al 1997). Others presented evidence that some hydrophobic agents, such as trifluoperazine, haloperidol and local anesthetics (Shoshan-Barmatz 1988;De Meis 1991;Wolosker et al 1992;Takara and Alonso 1996), promote Ca 2+ release from preloaded vesicles, more markedly in the absence of the ATPase ligands.…”

“…Others presented evidence that some hydrophobic agents, such as trifluoperazine, haloperidol and local anesthetics (Shoshan-Barmatz 1988;De Meis 1991;Wolosker et al 1992;Takara and Alonso 1996), promote Ca 2+ release from preloaded vesicles, more markedly in the absence of the ATPase ligands. Figure 4A Inhibitory effect of carticaine on the phosphorylation by Pi of the Ca 2+ -ATPase.…”

Characteristics of the Sarcoplasmic Reticulum Ca2+-dependent ATPase from Masticatory Muscles

“…Ca-ATPase activity increased when [Mg 2+ ] was increased until it reached a maximal value (Fig. 3B) and was then inhibited at higher concentrations, as described for the Ca-ATPase isolated from other muscle tissues (Takara and Alonso, 1996).…”