title: General anesthetic isoflurane modulates inositol 1,4,5-trisphosphate receptor calcium channel opening.
abstract: BACKGROUND
  Pharmacological evidence suggests that inhalational general anesthetics induce neurodegeneration in vitro and in vivo through overactivation of inositol trisphosphate receptor (InsP3R) Ca-release channels, but it is not clear whether these effects are due to direct modulation of channel activity by the anesthetics.
  
  
  METHODS
  Using single-channel patch clamp electrophysiology, the authors examined the gating of rat recombinant type 3 InsP3R (InsP3R-3) Ca-release channels in isolated nuclei (N = 3 to 15) from chicken lymphocytes modulated by isoflurane at clinically relevant concentrations in the absence and presence of physiological levels of the agonist inositol 1,4,5-trisphosphate (InsP3). The authors also examined the effects of isoflurane on InsP3R-mediated Ca release from the endoplasmic reticulum and changes in intracellular Ca concentration ([Ca]i).
  
  
  RESULTS
  Clinically relevant concentrations (approximately 1 minimal alveolar concentration) of the commonly used general anesthetic, isoflurane, activated InsP3R-3 channels with open probability similar to channels activated by 1 µM InsP3 (Po ≈ 0.2). This isoflurane modulation of InsP3R-3 Po depended biphasically on [Ca]i. Combination of isoflurane with subsaturating levels of InsP3 in patch pipettes resulted in at least two-fold augmentations of InsP3R-3 channel Po compared with InsP3 alone. These effects were not noted in the presence of saturating [InsP3]. Application of isoflurane to DT40 cells resulted in a 30% amplification of InsP3R-mediated [Ca]i oscillations, whereas InsP3-induced increase in [Ca]i and cleaved caspase-3 activity were enhanced by approximately 2.5-fold.
  
  
  CONCLUSIONS
  These results suggest that the InsP3R may be a direct molecular target of isoflurane and plays a role in the mechanisms of anesthetic-mediated pharmacological or neurotoxic effects.
authors.affiliation: From the Department of Anesthesiology and Critical Care (J.D.J., Y.P., H.W.) and Department of Physiology (D.-O.D.M., K.-H.C., H.V., J.K.F.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Current address: Department of Physiology, University of Hong Kong, Hong Kong, China (K.-H.C.).
authors.forename: J Donald
authors.initials: JD
authors.lastname: Joseph
authors.forename: Yi
authors.initials: Y
authors.lastname: Peng
authors.forename: Don-On Daniel
authors.initials: DO
authors.lastname: Mak
authors.forename: King-Ho
authors.initials: KH
authors.lastname: Cheung
authors.forename: Horia
authors.initials: H
authors.lastname: Vais
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Foskett
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D002645:Chickens; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects* / Q000502:physiology; D007530:Isoflurane / Q000494:pharmacology*; D051381:Rats
chemical_list: D018685:Anesthetics, Inhalation; D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007530:Isoflurane; D002118:Calcium