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Research Article

Voltage-dependent facilitation of Cx46 hemichannels

¹Clinica Alemana-Universidad del Desarrollo ²Texas Tech University Health Sciences Center

Submitted 15 June 2009 ; revised 27 October 2009 ; accepted in final form 27 October 2009

Gap junction channels are formed by two hemichannels in series (one from each neighboring cell), which are in turn connexin hexamers. Under normal conditions, hemichannels at the plasma membrane are mostly closed, but can be opened by changes in membrane voltage, extracellular divalent ion concentration, phosphorylation, pH and redox potential. Recently, interactions between channels have been found to modulate the activity of several ion channels, including gap junction channels. Here, we studied whether Cx46 hemichannels display such behavior. We studied the response of the Cx46 hemichannels expressed in Xenopus laevis oocytes to consecutive depolarization pulses. Hemichannels formed by wild-type Cx46 and a C-terminal domain truncation mutant (Cx46CT) were activated by voltage pulses. When the hemichannels were depolarized repeatedly from -60 mV to +80 mV, the amplitude of the outward and tail currents increased progressively with successive pulses. This phenomenon ("current facilitation") depended on the amplitude of the depolarization, reaching a maximum at ca. +60 mV in oocytes expressing Cx46, and on the interval between pulses, disappearing with intervals longer than about 20 s. The current facilitation was also present in oocytes expressing Cx46CT, ruling out a primary role of this domain in the facilitation. Nominal removal of divalent cations from the extracellular side caused maximal current activation of Cx46 and Cx46CT hemichannels and prevented facilitation. The results suggest that Cx46 hemichannels show a cooperative activation independent of their C-terminal domain.

connexins; gap junction channels; lens; ion channels