Connexin channel modulators and their mechanisms of action.
Electrical conduction in sheep Purkinje fibers has been blocked by three different procedures: (I) 1mm 2–4-dinitrophenol, (II) 3.5mm n-Heptan-1-ol (heptanol), and (III) treatment by a hypotonic (120 mOsmoles) Ca2+-free solution for half an hour, followed by return to normal conditions. The gap junction morphology was analyzed quantitatively in freezefracture replicas and compared in electrically conducting and nonconducting fibers. It is found that the three uncouplers of cell-to-cell conduction induce consistent and statistically significant alterations of the gap junction structure. The investigated morphological criteria: (a) P-face junctional particle diameter, control value 8.18±0.70 nm (mean±sd), (b) P-face junctional particles center-to-center spacing, control value 10.23±1.57 nm, and (c) E-face pits spacing, control value 9.45±0.98 nm, are, respectively, decreased to 7.46±0.62 nm, 9.25±1.34 nm and 8.67±1.13 nm in Purkinje fibers with complete conduction blocks. All three gap junctional dimensions are seen to decline progressively with time from the onset of an uncoupling treatment towards stable minima reached in half an hour. The observed morphological transitions appear related to the electrical uncoupling for the following reasons: partial electrical uncoupling results in values of the gap junctional dimensions that are intermediate between those measured in electrically coupled and uncoupled preparations, and the three morphological indices are seen to increase again towards control values very soon after electrical conduction has been re-established. It is concluded that the junctional channels closure on electrical uncoupling correlates with a measurable (−0.72±0.01 nm, difference of the means±se) decrease of the junctional particle diameters.