Regulation of neuronal K_Ca channels by β-neuregulin-1 does not require activation of Ras-MEK-extracellular signal-regulated kinase signaling cascades

Endogenous β-neuregulin-1 is required for the plasma membrane expression of large-conductance (BK-type) Ca²⁺-activated K ⁺ channels in developing chick ciliary neurons of the chick ciliary ganglion. During normal development, β-neuregulin-1 acts in concert with transforming growth factor-β1 to stimulate movement of large-conductance Ca²⁺-activated K⁺ channels from intracellular stores into the plasma membrane, although these two growth factors preferentially act on different intracellular pools. We have previously shown that actions of transforming growth factor-β1 on ciliary neurons require activation of phosphoinositol 3-kinase and Akt, as well as a parallel cascade composed of the small GTPase Ras and a mitogen-activated protein kinase (extracellular signal-regulated kinase). In addition, we have shown that the actions of β-neuregulin-1 require activation of phosphoinositol 3-kinase and the protein kinase Akt. Here we examine whether β-neuregulin-1-evoked mobilization of large-conductance Ca²⁺-activated K⁺ channels also requires activation of a Ras-extracellular signal-regulated kinase signaling cascade. We observed that application of β-neuregulin-1 caused a robust and MEK1/2-dependent increase in extracellular signal-regulated kinase diphosphorylation that indicates activation of this signaling cascade in ciliary ganglion neurons, similar to what we have previously observed for transforming growth factor-β1. However, activation of this cascade is not necessary for β-neuregulin-1-evoked mobilization because stimulation of macroscopic large-conductance Ca²⁺-activated K⁺ channels persisted in cells treated with the MEK1/2 inhibitors PD98059 or U0126, in cells over-expressing dominant-negative forms of extracellular signal-regulated kinase, and in cells treated with the Ras inhibitor FTI-277. These results indicate that the mechanisms that underlie β-neuregulin-1 and transforming growth factor-β1 mobilization of large-conductance Ca²⁺- activated K⁺ channels are only partly overlapping, possibly because they cause recruitment of spatially distinct signaling complexes.