Species specificity of mammalian connexin-26 to form open voltage-gated hemichannels.
Mutations of connexin-26 (Cx26) cause nonsyndromic hearing loss and other syndromes affecting ectoderm-derived tissues. While the exact mechanisms underlying these diseases remain elusive, Cx's are generally considered to mediate cell-to-cell communication by forming gap junction channels. We show here that unlike rat Cx26, human and sheep Cx26 form voltage-gated hemichannels when expressed in oocytes and Neuro2A cells. A single evolutionary amino acidic change at position 159 of the rodent protein, the replacement of aspartic acid with asparagine in the human and sheep proteins, accounts for this species specificity. At the resting potential and in normal millimolar extracellular calcium, open human Cx26 hemichannels can be detected both electrophysiologically and by dye uptake, although they did not affect cell viability. These hemichannels opened at approximately -50 mV and their activation increased by depolarization until they inactivate at positive membrane potentials. Single-channel analysis revealed that activation and inactivation involved two distinct voltage gating mechanisms and that the fully open hemichannel displays a conductance twice that of the intercellular channel. The existence of a hemichannel that opens under physiological control of the membrane potential may have important implications for the normal and pathological activity of Cx26 in humans, particularly with respect to hearing and the epidermis.
González
Daniel
D
Unit of Experimental Neurology, Research Department, Ramón y Cajal Hospital, Madrid, Spain.
Gómez-Hernández
Juan M
JM
Barrio
Luis C
LC
D000818:Animals; D000072259:Connexin 26; D017630:Connexins / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007473:Ion Channels / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D051381:Rats; D012756:Sheep; D013045:Species Specificity; D014981:Xenopus
D017630:Connexins; C000607045:GJB2 protein, Xenopus; C000607042:GJB2 protein, human; C000607044:Gjb2 protein, rat; D007473:Ion Channels; D000072259:Connexin 26