Gap junction channels: distinct voltage-sensitive and -insensitive conductance states

Abstract

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 (Vj) exceeding +/- 50 mV reduce junctional conductance (gj). However, substantial gj remains at even very large Vj values; this residual voltage-insensitive conductance has been termed gmin. We have explored the mechanism underlying gmin 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 gj (gmax) values ranging from < 2 to > 90 nS, the ratio gmin/gmax was found to be relatively constant (about 0.4-0.5), indicating that the channels responsible for the voltage-sensitive and -insensitive components of gj 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 gmin. We conclude that the voltage-insensitive component of gj 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.

Role of the Carboxyl Terminal of Connexin43 in Transjunctional Fast Voltage Gating

“…14,15 Recent studies have linked the existence of a residual state in the unitary channel behavior of connexins with the residual conductance observed from macroscopic gap junction currents during voltage gating (also referred to as G min ). 16 Furthermore, Anumonwo et al 17 recently reported that truncation of the CT domain of Cx40 was associated with the elimination of the residual state.…”

Gap Junction Localization and Connexin Expression in Cytochemically Identified Endothelial Cells of Arterial Tissue

“…The presence of three connexin types with distinct immunolabeling patterns in endothelia of different arteries has potentially important functional implications. Recent experimental studies on cells stably transfected with cDNAs encoding different connexins indicates that the properties of gap junction channels (e.g., unitary conductance, voltage sensitivity, molecular permeability, and ionic selectivity) vary according to the specific connexin expressed Elfgang et al 1995;Little et al 1995b;Veenstra et al 1995;Moreno et al 1994). In several (non-endothelial) cell types, the presence of more than one connexin has been documented within a given gap junctional plaque (Darrow et al 1995;Little et al 1995a;Sosinsky 1995;Gros et al 1994), raising the possibility that formation of heterotypic channels (comprising one connexon composed of one connexin type joined to a second connexon composed of a second connexin type) or heteromeric connexons (containing mixtures of connexins within a connexon) may contribute to the modulation of gap junction properties.…”

Connexin hemichannels and cell-cell channels: comparison of properties

“…How do the effects of pH on Cx46 hemichannels compare with those on Cx46 cellcell channels? It has been shown that gating of GJ channels by voltage is predominantly between the open state and a long-lived substate; the V j gating transitions are fast and typical of ion channel gating and complete closures are infrequent (11,12). However, complete closures can be induced by exposure to chemical uncouplers, such as H + or alkanols (13).…”