The physiological function of gap junction channels goes well beyond their initially discovered role in electrical synchronization of excitable cells. In most tissues, gap junction cells facilitate the exchange of second messengers and metabolites between cells. To test which parts of the channels formed by connexins determine the exclusion limit for the transit of molecules in the size range of second messengers and metabolites a domain exchange approach was used in combination with an accessibility assay for nonelectrolytes and flux measurements. The experimental results suggest that two open hemichannel forming connexins, Cx46 and Cx32E143, differ in accessibility and permeability. Sucrose is at the exclusion limit for Cx46 channels whereas sorbitol is at the exclusion limit for Cx32E143 channels. In chimeras between these connexins, where the first transmembrane segment M1 is exchanged, the exclusion limits correlate with those of the M1 donor. The same segregation was found in a separate study for the unitary conductance of the channels. Thus, conductance and permeability/ accessibility of the channels cosegregate with M1.
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