Pores in the Wall

Address correspondence to Shoichiro Tsukita, M.D., Ph.D., Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Tel.: 81-75-753-4372. Fax: 81-75-753-4660. E-mail:htsukita @mfour.med.kyoto-u.ac.jp 1 Abbreviations used in this paper: CPE, Clostridium perfringens enterotoxin; TJ, tight junction. In vertebrates, tight junctions (TJs) 1 play a central role in sealing the intercellular space in epithelial and endothelial cellular sheets (Schneeberger and Lynch, 1992; Gumbiner, 1993; Anderson and van Itallie, 1995). Without TJs, these cellular sheets cannot function as barriers to establish compositionally distinct fluid compartments. To maintain homeostasis, various materials must be selectively transported across these cellular sheets. Two distinct pathways are known for this transport: the transcellular and paracellular pathways in which materials move across plasma membranes and TJs, respectively (Spring, 1998; Fig. 1). The molecular machinery involved in transport through the transcellular pathway (i.e., channels, pumps, transporters, etc.) has been identified and well characterized in molecular terms. In sharp contrast, our knowledge regarding paracellular transport is limited mainly because of the lack of information on the molecular architecture of TJs. However, recent identification of TJ-specific integral membrane proteins prompted us to consider the molecular mechanism behind the barrier of TJs as well as transport across TJs. Fig. 1 shows the structural aspects of TJs. The key structure in TJs is the TJ strand (or fibril) within plasma membranes, which was visualized by freeze-fracture replica electron microscopy (Staehelin, 1973). Each TJ strand laterally and tightly associates with that in the apposing membrane of adjacent cells to form a paired strand, where the intercellular space is obliterated (so-called kissing points of plasma membranes in ultrathin sectional images; Farquhar and Palade, 1963). This paired strand has been suggested to be responsible for the intercellular sealing in epithelial/endothelial cellular sheets. Furthermore, detailed electrophysiological analyses suggested the existence of aqueous pores within the paired TJ strands (Fig. 1; Diamond, 1977; Claude, 1978; Reuss, 1992; Gumbiner, 1993). This mini-review will present an overview of the recent progress in our understanding of the structure and functions of TJ strands in molecular terms.