Connexin Specificity of Second Messenger Permeation: Real Numbers At Last

The discovery many years ago that ions and cytoplasmic molecules could diffuse between cells via gap junction channels inspired excited speculation about the roles such intercellular communication could play in development , physiology, and pathology. This view was reinforced when it later emerged that there are many types of gap junction channels, with ‫ف‬ 20 functionally distinct vertebrate isoforms of the component protein (con-nexin), which can combine in homomeric and hetero-meric channel structures that have distinct conductance, dye permeability, and gating properties. The unitary conductances range from 10 pS to 300 pS; their cation/ anion permeability ratios (P K+ / P Cl –) range from ‫ف‬ 8.0 to ‫ف‬ 0.8 and their permeabilities to fl uorescent tracers are highly disparate. None of these parameters correlate with each other (Harris, 2001). What is all this variability good for? It seems unlikely to be all about electrical coupling; it makes more sense to think that the distinct pore/permeability properties are important and perhaps designed for the ability to defi ne, mediate, and dynamically modulate the vocabulary of intercellular molecular signals. In fact, evidence for the importance of gap junction as conduits of intercellular molecular signals is growing. In recent years it has been demonstrated, in mostly qualitative ways, that different types of connexin channels have different effective permeabilities to specifi c cytoplasmic molecules, and that the permeability differences among connexin channels cannot be readily inferred from other known functional features. This work has increased speculation that (a) the pores of connexin channels are fi ne tuned for selectivity among specifi c cytoplasmic molecules, and (b) the connexin channels expressed at a particular cellular or tissue location are functionally selected for the ability to mediate highly specifi c intercellular signaling (i.e., for permeability to a specifi c second messenger, or for a specifi c spectrum of permeabilities among a set of second messengers). Several studies have inferred or determined per-channel permeabilities to second messengers, but quantitative data directly comparing the permeabilities of different junctional connexin channels to a second messenger have been lacking. The paper by Kanaporis et al. in this issue (see p. 2 9 3) provides such information; it reports the relative and absolute per-channel permea-bilities to cAMP of junctional channels formed by three different connexins (Cx26, Cx40, and Cx43). In addition, they provide, for each connexin studied, a quantitative relation between junctional conductance and cAMP per-meability and between permeability to …