TY - JOUR T1 - <strong>Membrane-mediated Activity of Local Anesthetics</strong> JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/molpharm.121.000252 SP - MOLPHARM-EMC-2021-000252 AU - Stephan Grage AU - Anke Culetto AU - Anne Ulrich AU - Stefan W. Weinschenk Y1 - 2021/01/01 UR - http://molpharm.aspetjournals.org/content/early/2021/09/02/molpharm.121.000252.abstract N2 - Abstract The activity of local anesthetics (LAs) has been attributed to the inhibition of ion channels. The concept of ligand recognition, however, does not explain the multitude of protein targets influenced by LAs. Here we review alternative functional models based on the indirect lipid-mediated effects of LAs on membrane proteins. Based on their amphiphilicity, LAs specifically immerse themselves into the bilayer membranes. LAs could cause anesthesia without having to directly bind to the receptor proteins by changing the physical properties of the lipid bilayer surrounding these proteins and ion channels. This could explain the numerous additional effects of LA besides anesthesia. It is conceivable that LAs act in one of the following ways: they (a) dissolve raft-like membrane micro-domains, (b) lower the lipid phase transition temperature and thereby affect nerve impulse propagation, or (c) modulate the lateral pressure profile of the lipid bilayer. Note that the two different concepts of membrane-mediated activity and binding to ion channels do not exclude each other. In fact, LA molecules can be regarded as the middle part of a continuum, ranging from entirely unspecific interactions of general anesthetics that act via dissolution in membranes, towards toxins with an exceptional affinity to highly specific binding sites. This comprehensive membrane-mediated model, describing a continuum of actions, offers a fresh perspective to clinical and pharmaceutical research and applications of local anesthetics. Significance Statement Local anesthetics belong to the most important drugs available to mankind. Their re-discovery as therapeutics, not only anesthetics, marks a milestone in global pain therapy. The membrane-mediated mechanism of action proposed in this review can explain their puzzling variety of target proteins and their as yet inexplicable therapeutic effects. The new concept presented here resolves these conundrums, by placing LAs into a continuum of structures and molecular mechanisms, namely in-between small general anesthetics and the more complex molecular toxins. ER -