Linked Life Data

10669313

Source:http://linkedlifedata.com/resource/pubmed/id/10669313

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2000-2-22
pubmed:abstractText
Local anaesthetics, in addition to anaesthesia, induce the synthesis of heat shock proteins (HSPs), sensitize cells to hyperthermia, and increase the aggregation of nuclear proteins during heat shock. Anaesthetics are membrane active agents, and anaesthesia appears to be due to altered ion channel activity; however, the direct effect of heat shock is protein denaturation. These observations suggest that local anaesthetics may sensitize cells to hyperthermia by interacting with and destabilizing membrane proteins such that protein denaturation is increased. It is shown, using differential scanning calorimetry (DSC), that the local anaesthetics procaine, lidocaine, tetracaine and dibucaine destabilize the transmembrane domains of the Ca2+ -ATPase of sarcoplasmic reticulum and the band III anion transporter of red blood cells. The transmembrane domain of the Ca2+ -ATPase has a transition temperature (Tm) of denaturation of 61 degrees C which is decreased, for example, to 53 degrees C by 15 mM lidocaine. The degree of destabilization (deltaTm) by each anaesthetic is proportional to the lipid to water partition coefficient, and the increased sensitization by anaesthetics with larger partition coefficients and at higher pH suggests that the uncharged forms of the anaesthetics are responsible for destabilization. A Hill analysis of deltaTm for the Ca2+ -ATPase as a function of the concentration of anaesthetic in water gives dissociation constants (Kd) on the order of 10(-4) M, if binding occurs directly from the aqueous phase. This demonstrates moderate affinity binding. However, dissociation constants of 1-3 M are obtained, if binding occurs through the lipid phase, which demonstrates low affinity binding. Thus, the interaction of local anaesthetics with the Ca2+ -ATPase may be moderately specific or non-specific depending on the mechanism of interaction. The observation that local anaesthetics also destabilize the transmembrane domain of the band III protein of erythrocytes suggests that destabilization of transmembrane proteins is a general property of anaesthetics, which is at least in part a mechanism of sensitization to hyperthermia.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0265-6736
pubmed:author
pubmed:issnType
Print
pubmed:volume
16
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1-17
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:articleTitle
Thermal destabilization of transmembrane proteins by local anaesthetics.
pubmed:affiliation
Guelph Waterloo Program for Graduate Work in Physics, University of Waterloo, Ontario, Canada.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.