GAP JUNCTION CHANNELS - DISTINCT VOLTAGE-SENSITIVE AND VOLTAGE-INSENSITIVE CONDUCTANCE STATES

All mammalian gap junction channels are sensitive to the voltage difference imposed across the junctional membrane, and parameters of voltage sensitivity have been shown to vary according to the gap junction protein that is expressed. For connexin43, the major gap junction protein in the cardiovascular system, in the uterus, and between glial cells in brain, voltage clamp studies have shown that transjunctional voltages (V-j) exceeding +/-50 mV reduce junctional conductance (g(j)). However, substantial g; remains at even very large V-j values; this residual voItage-insensitive conductance has been termed g(min). We have explored the mechanism underlying g(min) using several cell types in which connexin43 is endogenously expressed as well as in communication-deficient hepatoma cells transfected with cDNA encoding human connexin43. For pairs of transfectants exhibiting series resistance-corrected maximal g(j) (g(max)) values ranging from <2 to >90 nS, the ratio g(min)/g(max) was found to be relatively constant (about 0.4-0.5), indicating that the channels responsible for the voltage-sensitive and -insensitive components of g, are not independent. Single channel studies further revealed that different channel sizes comprise the voltage-sensitive and -insensitive components, and that the open times of the larger, more voltage-sensitive conductance events declined to values near zero at large voltages, despite the high g(min). We conclude that the voltage-insensitive component of g(j) is ascribable to a voltage-insensitive substate of connexin43 channels rather than to the presence of multiple types of channels in the junctional membrane. These studies thus demonstrate that for certain gap junction channels, closure in response to specific stimuli may be graded, rather than all-or-none.