The Un(f)told Story of General Anesthesia

• Published in: Chembiochem : a European journal of chemical biology 2018-05, Vol.19 (9), p.895-901
• Main Author: Zsila, Ferenc
• Format: Article
• Language: English
• Subjects: Anesthesia; Anesthetics; Chloroform; Cognitive ability; Gene expression; hexafluoroisopropanol; Immunosuppressive agents; inhalational anesthetics; intrinsic disorder; ion channels; Metastases; Molecular chains; Molecular modelling; Pharmacology; Protein folding; Protein structure; Proteins; Secondary structure; Signaling; Trifluoroethanol; Tumor cells; Tumors
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201700691

Inhalational anesthetics are routinely employed in clinical practice to accomplish general anesthesia. Concerns have recently emerged regarding the deleterious impact of these volatile agents on cognitive performance, immune functions, and tumor recurrence and metastasis. These agents have been shown to modify the gene‐expression pattern as well as cell signaling in tumor cells, but the underlying molecular mechanisms remain a matter of conjecture. Regulatory/signaling proteins either of cytosolic or membrane origin abundantly contain intrinsically disordered sequences, the conformational pliability of which is pivotal in their biological functions. It is well known that chloroform (an anesthetic itself), trifluoroethanol, hexafluoroisopropanol, and related haloalcohols markedly affect the structure of disordered proteins and protein regions by inducing folding, misfolding, or even aggregation. Taking into consideration the physicochemical similarities and protein interaction modes of these volatile solvents and inhaled anesthetics, it is postulated that administration of these drugs can also modify the secondary structure of disordered protein segments. Accordingly, pharmacological effects of anesthetics may, at least in part, be mediated by conformational perturbations of intrinsic disorder‐based regulatory protein networks of cells. Disordered dreams: In analogy to the effects of volatile fluoroalcohols, inhalational anesthetics might also perturb the conformation of intrinsically disordered protein sequences. Hence, halogenated anesthetics can modulate the protein–protein and protein–nucleic acid interactome and, thus, the biochemical actions of a variety of signaling and regulatory proteins contributing to desired and undesired anesthesia end points.