The molecular basis of selective permeability of connexins is complex and includes both size and charge

Abstract

Although gap junction channels are still widely viewed as large, nonspecific pores connecting cells, the diversity in the connexin family has led more attention to be focused on their permeability characteristics. We summarize here the current status of these investigations, both published and on-going, that reveal both charge and size selectivity between gap junction channels composed of different connexins. In particular, this review will focus on quantitative approaches that monitor the expression level of the connexins, so that it is clear that differences that are seen can be attributed to channel properties. The degree of selectivity that is observed is modest compared to other channels, but is likely to be significant for biological molecules that are labile within the cell. Of particular relevance to the in vivo function of gap junctions, recent studies are summarized that demonstrate that the connexin phenotype can control the nature of the endogenous traffic between cells, with consequent effects on biological effects of gap junctions such as tumor suppression.

Putting tumours in context

“…The particular composition of CONNEXIN subunits within a gap junction determines the type of molecule that can be transported 16 . Much remains to be learned about how the specific combination of connexins facilitates tissue interactions, but it is clear, again, that generalizations should be avoided, as the expression patterns (and probably the function) of connexins are tissue dependent and change during tumour progression 17,18 .…”

Mathematical model of morphogen electrophoresis through gap junctions

“…When open, intercellular channels are generally permeable to molecules of less than 1 kDa (Loewenstein, 1981), but the exact permeability is a function of (1) precisely which connexin family members form the junction (White and Bruzzone, 1996), (2) the charge and size of the permeant molecule (Landesman et al, 2000;Nicholson et al, 2000), (3) the pH of cytoplasmic and intercellular space (Morley et al, 1997), (4) transjunctional and membrane voltage of the cells (Brink, 2000), (5) the phosphorylation state of the connexin protein subunits (Lampe and Lau, 2000), and (6) the activities of several chemical gating molecules (Granot and Dekel, 1998). Thus, functional GJC is dependant on the existence of compatible hemichannels on the cells' surfaces, the permeability of the hemichannels to the substance, and the open status of the gap junction.…”

“…Other possible developmental systems where such models may be relevant include Drosophila imaginal disks and the chick limb (Weir and Lo, 1984;Coelho and Kosher, 1991). The proposed electrophoretic mechanism may also be related to dipolar alignment of long, thin molecules larger than the usual 1-kDa limit to facilitate their passage through gap junction channels (Woodruff, 2005) and will have to incorporate knowledge of the specific types of GJ present in a given tissue as well as the nature of putative morphogens, as radically different permeabilities of gap junctions to different types of molecules have been reported (Bevans et al, 1998;Goldberg et al, 1999Goldberg et al, , 2002Nicholson et al, 2000). Ultimately, it will be necessary to incorporate not only upstream mechanisms responsible for generating the voltage gradients but also downstream mechanisms by which gradients are sensed by cell fields and transduced into stable cascades of differential gene expression.…”

Sharing signals: connecting lung epithelial cells with gap junction channels

“…One of the best approaches is to measure permselectivity, where the net ionic flux is measured electrophysiologically simultaneously with fluorescent dye transfer measured by fluorescence microscopy (40,275,280). This provides a means for the investigator to normalize for total gap junction channel cross-sectional area, while at the same time measuring permeability of dyes with distinct mass and charge (80,204). Other approaches include measuring simultaneous transfer of multiple dyes (148,204) and/or radiolabeled metabolites (100).…”

“…This provides a means for the investigator to normalize for total gap junction channel cross-sectional area, while at the same time measuring permeability of dyes with distinct mass and charge (80,204). Other approaches include measuring simultaneous transfer of multiple dyes (148,204) and/or radiolabeled metabolites (100).…”