Academic journal article Genetics

Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast

Academic journal article Genetics

Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast

Article excerpt

ANESTHETICS have been used clinically for over 160 years, but their mechanism of action remains unclear because of difficulty in explaining why anesthetics with widely varying structures can cause similar effects (Urban et al. 2006). Lipid and protein theories have been proposed to explain the mechanism and have been debated for many years (Antkowiak 2001). The lipid theory was proposed to explain the Meyer-Overton rule, which states that the anesthetic potency of various anesthetics correlates with their lipophilicity (hydrophobicity), and it assumes that membrane lipids are the hydrophobic sites of nonspecific interactions with anesthetics (Meyer 1899). However, this theory does not explain why nonspecific interactions with membranes that affect numerous targets result in a specific phenotype such as anesthesia. Therefore, the protein theory was proposed to explain several other observations, including a contradiction of the Meyer-Overton rule. This theory assumes that anesthetics interact specifically with proteins, and it suggests that specific target proteins have anesthetic-binding pockets of limited size as their hydrophobic sites (Franks and Lieb 1990). To date, numerous neurotransmitter receptors and ion channels have been identified as relevant targets (Antkowiak 2001; Urban et al. 2006). Antipsychotic effect has been found initially for chlorpromazine (CPZ), a phenothiazine (Laborit et al. 1952). A dopamine D2 receptor was considered to be the target for CPZ at an early stage (Snyder et al. 1974), but numerous targets for phenothiazines have now been identified (Prozialeck and Weiss 1982; Ogata et al. 1989; Mozrzymas et al. 1999). According to the protein theory, the large number of possible targets for anesthetics and phenothiazines raises a question about interactions with specific receptors or channels. Therefore, the mechanisms of action of these clinical drugs remain unclear. One reason why crucial targets cannot be determined is the difficulty in demonstrating correlations between drugs and high-order biological phenomena such as anesthesia and psychiatric effects.

Quaternary ammonium compounds (QACs), which are representative cationic surfactants, have potent antibiotic effects. The destruction of membranes by surfactant activity accounts for the antibiotic-effect mechanism at high concentrations, but the antibiotic-effect mechanism at lower concentrations, where membranes are not destroyed, remains unknown (Wessels and Ingmer 2013). Structures of local anesthetics, phenothiazines, alcohols, and QACs are largely different, but they are all amphiphiles and thus, at high concentrations, have sufficient surfactant-like activity to lyse erythrocytes (Seeman 1972; Sheetz and Singer 1974), model membranes (Kitagawa et al. 2004), and the budding yeast Saccharomyces cerevisiae (Uesono et al. 2008, 2011). This activity accounts for the common toxicity of these compounds at high concentrations. At low concentrations that do not cause cell lysis, these compounds induce similar responses, including the inhibition of both translation initiation and polarization of the actin cytoskeleton, nuclear localization of the stress-responsible transcription factor Msn2, and processingbody (P-body) formation for messenger RNA (mRNA) decay in a dose-dependent manner in yeast (Uesono et al. 2008, 2011; Araki et al. 2015). Volatile anesthetics (Bruce 1975; Heys et al. 1989; Horber et al. 1988), local anesthetics (Banerjee and Redman 1977; Wang et al. 2011), and phenothiazines (Raghupathy et al. 1970; Kumar et al. 1991) are known to inhibit protein synthesis in animals at cellular, tissue, and whole-body levels. Because volatile anesthetics inhibit translation initiation in yeast (Palmer et al. 2005), inhibition of protein synthesis would be an important response that is common to these compounds irrespective of species. Thus, the question remains: how do these compounds with widely varying structures induce similar effects? We consider that the amphiphilic structure that is common to these compounds, rather than their detailed structures, induces these responses at low concentrations (Uesono 2009). …

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