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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 6, 2005; DOI: 10.1124/jpet.105.092213

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Received for publication July 12, 2005.
Revised August 31, 2005.
Accepted for publication August 31, 2005.

Visualization of Binding and Transcytosis of Botulinum Toxin by Human Epithelial Cells

Chowdhury R. Ahsan 1, Gyorgy Hajnoczky 2, Andrew B. Maksymowych 1, Lance L. Simpson 1*

1 Jefferson Medical College 2 Thomas Jefferson University

* Address correspondence to: E-mail: lance.simpson{at}jefferson.edu

Abstract

Botulinum toxin is an unusually potent oral poison, which means that the toxin must have an efficient mechanism for escaping the lumen of the gut to reach the general circulation. Previous work involving iodination of toxin and analysis of its movement demonstrated a specific process of transepithelial transport. In the present study, botulinum toxin labeled with Alexa FluorTM 488 was used to visualize the discrete steps of binding, internalization, transcytosis and release. The data revealed that binding sites for the toxin were distributed across the apical surface of epithelial cells, and there was no evidence of significant clustering. The amount of toxin bound to receptors at saturation was too large to be accommodated in a single wave of endocytosis. Toxin that entered epithelial cells did not remain in the vicinity of the endocytosing membrane, which is in striking contrast to events in neuronal cells. Instead, the toxin began to spread across the length of cells, eventually being released on the basolateral surface. Migration of toxin through epithelial cells required redistribution to the cell periphery. This migration pattern could be attributed to the large and centrally located nucleus, which physically displaced transport vesicles. Transcytosed toxin began to reach the contralateral surface within ca. 5 min, and transcytosis was essentially complete within 20 to 30 min.


Key words: Absorption, Alexa Fluor 488, Botulinum toxin, Confocal microscopy, Epithelial cell, Transcytosis


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