AN ETHER-A-GO-GO K-EAG, CONTRIBUTES TO THE HYPERPOLARIZATION OF HUMANFUSION-COMPETENT MYOBLASTS( CURRENT, IH)

1. Two early signs of human myoblast commitment to fusion are membrane potential hyperpolarization and concomitant expression of a non-inact ivating delayed rectifier K+ current, I-K(NI). This current closely re sembles the outward K+ current elicited by rat ether-a-go-go (r-eag) c hannels in its range of potential for activation and unitary conductan ce. 2. It is shown that activation kinetics of I-K(NI), like those of r-eag, depend on holding potential and on [Mg2+](o), and that I-K(NI), like r-eag, is reversibly inhibited by a rise in [Ca2+](i). 3. Forced expression of an isolated human ether-a-go-go K+ channel (h-eag) cDNA in undifferentiated myoblasts generates single-channel and whole-cell currents with remarkable similarity to I-K(NI). 4. h-eag current (Ih- eag) is reversibly inhibited by a rise in [Ca2+](i), and the activatio n kinetics depend on holding potential and [Mg2+](o). 5. Forced expres sion of h-eag hyperpolarizes undifferentiated myoblasts from -9 to -50 mV, the threshold for the activation of both I h-eag and I-K(NI). Sim ilarly, the higher the density of I-K(NI), the more hyperpolarized the resting potential of fusion-competent myoblasts. 6. It is concluded t hat h-eag constitutes the channel underlying I-K(NI), and that it cont ributes to the hyperpolarization of fusion-competent myoblasts. To our knowledge, this is the first demonstration of a physiological role fo r a mammalian eag K+ channel.