Mechanism of local anesthetic-induced disruption of raft-like ordered membrane domains

Research output: Contribution to journalArticle

Abstract

Background: Because ordered membrane domains, called lipid rafts, regulate activation of ion channels related to the nerve pulse, lipids rafts are thought to be a possible target for anesthetic molecules. To understand the mechanism of anesthetic action, we examined influence of representative local anesthetics (LAs); dibucaine, tetracaine, and lidocaine, on raft-like liquid-ordered (Lo)/non-raft-like liquid-disordered (Ld) phase separation. Methods: Impact of LAs on the phase separation was observed by fluorescent microscopy. LA-induced perturbation of the Lo and Ld membranes was examined by DPH anisotropy measurements. Incorporation of LAs to the membranes was examined by fluorescent anisotropy of LAs. The biding location of the LAs was indicated by small angle x-ray diffraction (SAXD). Results: Fluorescent experiments showed that dibucaine eliminated the phase separation the most effectively, followed by tetracaine and lidocaine. The disruption of the phase separation can be explained by their disordering effects on the Lo membrane. SAXD and other experiments further suggested that dibucaine's most potent perturbation of the Lo membrane is attributable to its deeper immersion and bulky molecular structure. Tetracaine, albeit immersed in the Lo membrane as deeply as dibucaine, less perturbs the Lo membrane probably because of its smaller bulkiness. Lidocaine hardly reaches the hydrophobic region, resulting in the weakest Lo membrane perturbation. Conclusion: Dibcaine perturbs the Lo membrane the most effectively, followed by tetracaine and lidocaine. This ranking correlates with their anesthetic potency. General significance: This study suggests a possible mechanistic link between anesthetic action and perturbation of lipid rafts.

Original languageEnglish
Pages (from-to)1381-1389
Number of pages9
JournalBiochimica et Biophysica Acta - General Subjects
Volume1863
Issue number9
DOIs
Publication statusPublished - Sep 1 2019

Fingerprint

Liquid membranes
Local Anesthetics
Dibucaine
Tetracaine
Membranes
Lidocaine
Phase separation
Anesthetics
Lipids
Anisotropy
Liquids
Diffraction
X rays
X-Rays
Ion Channels
Molecular structure
Immersion
Microscopic examination
Molecular Structure
Experiments

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Mechanism of local anesthetic-induced disruption of raft-like ordered membrane domains. / Kinoshita, Masanao; Chitose, Takeshi; Matsumori, Nobuaki.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1863, No. 9, 01.09.2019, p. 1381-1389.

Research output: Contribution to journalArticle

@article{67be36fd7cf0413d9a27f1b090a0eef2,
title = "Mechanism of local anesthetic-induced disruption of raft-like ordered membrane domains",
abstract = "Background: Because ordered membrane domains, called lipid rafts, regulate activation of ion channels related to the nerve pulse, lipids rafts are thought to be a possible target for anesthetic molecules. To understand the mechanism of anesthetic action, we examined influence of representative local anesthetics (LAs); dibucaine, tetracaine, and lidocaine, on raft-like liquid-ordered (Lo)/non-raft-like liquid-disordered (Ld) phase separation. Methods: Impact of LAs on the phase separation was observed by fluorescent microscopy. LA-induced perturbation of the Lo and Ld membranes was examined by DPH anisotropy measurements. Incorporation of LAs to the membranes was examined by fluorescent anisotropy of LAs. The biding location of the LAs was indicated by small angle x-ray diffraction (SAXD). Results: Fluorescent experiments showed that dibucaine eliminated the phase separation the most effectively, followed by tetracaine and lidocaine. The disruption of the phase separation can be explained by their disordering effects on the Lo membrane. SAXD and other experiments further suggested that dibucaine's most potent perturbation of the Lo membrane is attributable to its deeper immersion and bulky molecular structure. Tetracaine, albeit immersed in the Lo membrane as deeply as dibucaine, less perturbs the Lo membrane probably because of its smaller bulkiness. Lidocaine hardly reaches the hydrophobic region, resulting in the weakest Lo membrane perturbation. Conclusion: Dibcaine perturbs the Lo membrane the most effectively, followed by tetracaine and lidocaine. This ranking correlates with their anesthetic potency. General significance: This study suggests a possible mechanistic link between anesthetic action and perturbation of lipid rafts.",
author = "Masanao Kinoshita and Takeshi Chitose and Nobuaki Matsumori",
year = "2019",
month = "9",
day = "1",
doi = "10.1016/j.bbagen.2019.06.008",
language = "English",
volume = "1863",
pages = "1381--1389",
journal = "Biochimica et Biophysica Acta - General Subjects",
issn = "0304-4165",
publisher = "Elsevier",
number = "9",

}

TY - JOUR

T1 - Mechanism of local anesthetic-induced disruption of raft-like ordered membrane domains

AU - Kinoshita, Masanao

AU - Chitose, Takeshi

AU - Matsumori, Nobuaki

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Background: Because ordered membrane domains, called lipid rafts, regulate activation of ion channels related to the nerve pulse, lipids rafts are thought to be a possible target for anesthetic molecules. To understand the mechanism of anesthetic action, we examined influence of representative local anesthetics (LAs); dibucaine, tetracaine, and lidocaine, on raft-like liquid-ordered (Lo)/non-raft-like liquid-disordered (Ld) phase separation. Methods: Impact of LAs on the phase separation was observed by fluorescent microscopy. LA-induced perturbation of the Lo and Ld membranes was examined by DPH anisotropy measurements. Incorporation of LAs to the membranes was examined by fluorescent anisotropy of LAs. The biding location of the LAs was indicated by small angle x-ray diffraction (SAXD). Results: Fluorescent experiments showed that dibucaine eliminated the phase separation the most effectively, followed by tetracaine and lidocaine. The disruption of the phase separation can be explained by their disordering effects on the Lo membrane. SAXD and other experiments further suggested that dibucaine's most potent perturbation of the Lo membrane is attributable to its deeper immersion and bulky molecular structure. Tetracaine, albeit immersed in the Lo membrane as deeply as dibucaine, less perturbs the Lo membrane probably because of its smaller bulkiness. Lidocaine hardly reaches the hydrophobic region, resulting in the weakest Lo membrane perturbation. Conclusion: Dibcaine perturbs the Lo membrane the most effectively, followed by tetracaine and lidocaine. This ranking correlates with their anesthetic potency. General significance: This study suggests a possible mechanistic link between anesthetic action and perturbation of lipid rafts.

AB - Background: Because ordered membrane domains, called lipid rafts, regulate activation of ion channels related to the nerve pulse, lipids rafts are thought to be a possible target for anesthetic molecules. To understand the mechanism of anesthetic action, we examined influence of representative local anesthetics (LAs); dibucaine, tetracaine, and lidocaine, on raft-like liquid-ordered (Lo)/non-raft-like liquid-disordered (Ld) phase separation. Methods: Impact of LAs on the phase separation was observed by fluorescent microscopy. LA-induced perturbation of the Lo and Ld membranes was examined by DPH anisotropy measurements. Incorporation of LAs to the membranes was examined by fluorescent anisotropy of LAs. The biding location of the LAs was indicated by small angle x-ray diffraction (SAXD). Results: Fluorescent experiments showed that dibucaine eliminated the phase separation the most effectively, followed by tetracaine and lidocaine. The disruption of the phase separation can be explained by their disordering effects on the Lo membrane. SAXD and other experiments further suggested that dibucaine's most potent perturbation of the Lo membrane is attributable to its deeper immersion and bulky molecular structure. Tetracaine, albeit immersed in the Lo membrane as deeply as dibucaine, less perturbs the Lo membrane probably because of its smaller bulkiness. Lidocaine hardly reaches the hydrophobic region, resulting in the weakest Lo membrane perturbation. Conclusion: Dibcaine perturbs the Lo membrane the most effectively, followed by tetracaine and lidocaine. This ranking correlates with their anesthetic potency. General significance: This study suggests a possible mechanistic link between anesthetic action and perturbation of lipid rafts.

UR - http://www.scopus.com/inward/record.url?scp=85067898471&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067898471&partnerID=8YFLogxK

U2 - 10.1016/j.bbagen.2019.06.008

DO - 10.1016/j.bbagen.2019.06.008

M3 - Article

AN - SCOPUS:85067898471

VL - 1863

SP - 1381

EP - 1389

JO - Biochimica et Biophysica Acta - General Subjects

JF - Biochimica et Biophysica Acta - General Subjects

SN - 0304-4165

IS - 9

ER -