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Cover  A number of membrane proteins, including acetylcholine receptors, certain aquaporins, tight junction subunits, and gap junction (GJ) channels, arrange extensively into densely packed clusters, arrays, or strands in the plasma membrane. However, how these multiunit structures are assembled and new units added has remained largely elusive. Two recent papers (Gaietta et al. (2002) Science 296, 503-507; Lauf et al. (2002) Proc. Natl. Acad. Sci. USA 99, 10446-10451) finally elucidate how GJ channels, the ubiquitous structures known to mediate direct cell-to-cell communication, are delivered to and removed from the channel clustersan issue that had remained unresolved since the morphological characterization of GJs by freeze-fracture electron microscopy, more than 30 years ago. Lauf et al. studied GJs in living cells that were assembled from the GJ subunit protein connexin43, which they tagged with green fluorescent protein (GFP), and a technique termed "fluorescence recovery after photo-bleaching" (FRAP), while Gaietta et al. studied the distribution of connexin43 that was successively labeled with two different colors of biarsenic compounds (see Falk (2002) Trends Cell Biol. 12, 399-404 for more information on GJs and these techniques). Both articles demonstrate that newly synthesized channels were added to the outer margins of the channel clusters, while older channels were removed simultaneously from the plaque center. Multicolor time lapse microscopy performed by Lauf et al. further revealed that GJ hemichannels (connexons) were delivered in vesicular carriers that traveled along microtubules from the Golgi to reach the plasma membrane. Plasma membrane connexons could then move laterally and thus reach the outer margins of the channel clusters, where the opposing plasma membranes were close enough to allow connexons to dock into complete double-membrane-spanning GJ channels. Collectively, these new results explain how connexons can first function in intra- and extracellular signaling, as discovered recently (Quist et al. (2002) J. Cell Biol. 148, 1063-1074; Kamermans et al. (2001) Science 292, 1178-1180; Contreras et al. (2002) Proc. Natl. Acad. Sci. USA 99, 495-500), prior to GJ channel formation and their well documented role in direct cell-to-cell communication. The cover shows a GJ channel cluster assembled from connexin43-GFP, viewed on its plane surface 1 hr after GFP-fluorescence of a square area (boxed in the top insert) was permanently photo-bleached. Newly synthesized channels added to the cluster are visible as a fluorescent rim outlining the bleached channels. The same channel cluster just before (upper) and 1 min after (lower) photo-bleaching is shown in the inserts.Matthias M. Falk