Cx46 hemichannels contribute to the sodium leak conductance in lens fiber cells

Abstract

The lens is proposed to have an internal microcirculation system consisting of continuously circulating ionic fluxes that play an essential role in maintaining lens transparency. One of the key components of this system is the sodium leak conductance. Here we investigate the contribution of Cx46 hemichannels to the basal membrane permeability of peripheral fiber cells isolated from transgenic mouse lenses lacking Cx50 or both Cx50 and Cx46 (dKO) using the whole cell patch-clamp technique. Our results show that Cx46 hemichannels were largely closed at a resting voltage of -60 mV in the presence of millimolar divalent cation concentrations. However, even though the vast majority of these channels were closed at -60 mV, a small, persistent, inward current could still be detected. This current could be mostly blocked by exposure to 1 mM La(3+) and was not observed in fiber cells isolated from dKO mouse lenses suggesting that it was due to Cx46 hemichannels. In addition, Cx50(-/-) fiber cells showed increased open channel noise and a depolarized resting potential compared with dKO fiber cells. Exposure of Cx50(-/-) fiber cells to La(3+) hyperpolarized the resting potential to -58 mV, which is similar to the value of resting potential measured in dKO fiber and significantly reduced the open channel noise. In conclusion, these results suggest that Cx46 hemichannels may contribute to the sodium leak conductance in lens fiber cells.

The cause and consequence of fiber cell compaction in the vertebrate lens

“…Lens Na/K-ATPase is concentrated in the equatorial epithelium, while sodium “leak” channels (perhaps comprised of connexin hemichannels (Ebihara et al, 2014)) are located in the plasma membranes of inner fiber cells. This arrangement leads to the generation of a circulating sodium current (Mathias, 1985).…”

Diseases associated with leaky hemichannels

“…This suggests that mutation Cx46G143R induces an important increase in the HC activity, possibly by modifying the interaction between the CT and IL, which is associated with HC opening ( Ren et al, 2013 ). A possible explanation for the pathological mechanism of leaky Cx46 HCs is that the opening of these channels produces an excessive flow of Ca 2+ through the plasma membrane ( Ebihara et al, 2014 ; Mandal et al, 2015 ), which should perturb the normal ionic balance of lens cells ( Figure 3 ).…”

Focus on lens connexins

“…Ebihara et al showed opening of Cx46 hemichannels in isolated lens fiber cells studied at reduced or at normal extracellular Ca 2+ concentrations [ 44 , 45 ]. The opening of Cx46 hemichannels at physiological concentrations of Ca 2+ may contribute to the Na + leak conductance [ 45 ] and provide a pathway for the inward cation leak of the lens circulation model [ 46 ]. Because Cx46 hemichannels are mechanosensitive, it has been proposed that they participate in lens accommodation [ 47 ].…”