Hemichannel composition and electrical synaptic transmission: molecular diversity and its implications for electrical rectification

Abstract

Unapposed hemichannels (HCs) formed by hexamers of gap junction proteins are now known to be involved in various cellular processes under both physiological and pathological conditions. On the other hand, less is known regarding how differences in the molecular composition of HCs impact electrical synaptic transmission between neurons when they form intercellular heterotypic gap junctions (GJs). Here we review data indicating that molecular differences between apposed HCs at electrical synapses are generally associated with rectification of electrical transmission. Furthermore, this association has been observed at both innexin and connexin (Cx) based electrical synapses. We discuss the possible molecular mechanisms underlying electrical rectification, as well as the potential contribution of intracellular soluble factors to this phenomenon. We conclude that asymmetries in molecular composition and sensitivity to cellular factors of each contributing hemichannel can profoundly influence the transmission of electrical signals, endowing electrical synapses with more complex functional properties.

Keywords: asymmetry; connexin; electrical synapse; gap junction; innexin; rectification.

Figure 1

Channels formed by connexin and innexin proteins can play functional roles as single “hemichannels” (HCs) or assemble into intercellular channels at gap junctions to provide cell-cell communication. (A) Hemichannels can be molecularly different (note difference in color and shape) and act as conduits for the release of messenger molecules. (B) Identical HCs can assemble into intercellular “homotypic” gap junction channels. (C) Hemichannels of different molecular composition can assemble into intercellular “heterotypic” gap junction channels.

Figure 2

Directionality and symmetry in electrical transmission. (A) Determinants of the strength of electrical transmission. The amplitude of the coupling potential, defined by the coupling coefficients in each direction (CC₁ & CC₂), once the capacitance of the membrane has been charged, is determined by both the resistance of the junction (R_j) and the resistances of the coupled cells (R₁ & R₂). (B) Electrical transmission is symmetric in cells with similar R and non-rectifying junctions (constant R_j). (C) Rectifying junctions make electrical transmission between neurons with similar R asymmetric. (D) Cells with different R create asymmetry of electrical transmission when junctions are non-rectifying. (E) Electrical transmission could be symmetric in cells with different R and rectifying junctions if the effects cancel each other. (F) The combination of differences in R and rectifying junctions can create strong asymmetry of electrical transmission for some polarities.

Figure 3

Hemichannel composition determines the symmetry of electrical transmission. (A) Homotypic gap junction channels that comprise symmetric charge distribution with respect to the pore center of the channel, behave as passive resistors with symmetric junctional conductance (g_j) over transjunctional voltage (V_j) dependence (normalized to g_j value at V_j equal zero). (B) Heterotypic gap junction channels that comprise an asymmetry in positive and negative charge distribution with respect to the pore center of the channel behave as electrical rectifiers (p-n junction) with steep asymmetric g_j-V_j dependence. Normally, depolarizing (positive) potentials are more easily transmitted from the cell with negatively charged HCs to the cell with positively charged HCs.

Figure 4

Hemichannel composition and intercellular gradient of charged cytosolic factors can lead to rectification of electrical transmission. (A,B) Heterotypic gap junction channels with steep asymmetric g_j-V_j dependence (A) facilitate or attenuate the electrical transmission of depolarizing (positive) potentials from Cell 1 to Cell 2 (1→2) or 1←2, respectively (B). The same junctions facilitate or attenuate the electrical transmission of hyperpolarizing (negative) potentials from 1←2 or 1→2, respectively (B). (C,D) Transjunctional gradient of free magnesium ion concentration ([Mg²⁺]_i) induces asymmetric g_j-V_j dependence in homotypic gap junction channels (C) that are hypersensitive to [Mg²⁺]_i, such as Cx36 gap junction channels. Electrical transmission of depolarizing potentials is facilitated from 2→1 (D), which is the opposite direction of the transjunctional [Mg²⁺]_i gradient (1→2). The same transjunctional [Mg²⁺]_i gradient facilitates the electrical transmission of hyperpolarizing potentials from 1→2 (D).

Figure 5

Possible mechanisms underlying electrical rectification at electrical synapses. (A) Steep electrical rectification can be attainable by the separation of fixed positive and negative charges at opposite ends of heterotypic gap junction channels (p-n junction) resulting from asymmetries in the molecular composition of the HCs. (B) Electrical rectification can also result from the presence of an intercellular gradient of charged cytosolic factors, such as Mg²⁺ and spermine, which alter channel conductance. Molecular diversity can make some channels more susceptible of interacting with certain cytosolic factors. (C) Complex electrical rectification can arise from the combination of both mechanisms.