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Mar. Drugs 2010, 8, 219-234; doi:10.3390/md8020219 OPEN ACCESS Marine Drugs ISSN 1660-3397 /journal/marinedrugs Review The Tetrodotoxin Binding Site Is within the Outer Vestibule of the Sodium Channel Harry A. Fozzard * and Gregory M. Lipkind Department of Medicine, MC 6094, University of Chicago Hospitals, 5841 S Maryland Av. Chicago, IL 60637, USA; E-Mail: lipkind@ * Author to whom correspondence should be addressed; E-Mail: hafozzar@; Tel.: +1-828-685-3044; Fax: +1-828-685-8701. Received: 23 December 2009; in revised form: 10 January 2010 / Accepted: 28 January 2010 / Published: 1 February 2010 Abstract: Tetrodotoxin and saxitoxin are small, compact asymmetrical marine toxins that block voltage-gated Na channels with high affinity and specificity. They enter the channel pore’s outer vestibule and bind to multiple residues that control permeation. Radiolabeled toxins were key contributors to channel protein purification and subsequent cloning. They also helped identify critical structural elements called P loops. Spacial organization of their mutation-identified interaction sites in molecular models has generated a molecular image of the TTX binding site in the outer vestibule and the critical permeation and selectivity features of this region. One site in the channel’s domain I P loop determines affinity differences in mammalian isoforms. Keywords: marine toxins; Na channels; molecular modeling 1. Introduction Tetrodotoxin (TTX) and saxitoxin (STX)—guanidinium toxins—are potent and potentially