Regulation of neuronal K(Ca) channels by beta-neuregulin-1 does not require activation of Ras-MEK-extracellular signal-regulated kinase signaling cascades.
Endogenous beta-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, beta-neuregulin-1 acts in concert with transforming growth factor-beta1 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-beta1 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 beta-neuregulin-1 require activation of phosphoinositol 3-kinase and the protein kinase Akt. Here we examine whether beta-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 beta-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-beta1. However, activation of this cascade is not necessary for beta-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 beta-neuregulin-1 and transforming growth factor-beta1 mobilization of large-conductance Ca2+-activated K+ channels are only partly overlapping, possibly because they cause recruitment of spatially distinct signaling complexes.
Chae
K-S
KS
Department of Biology and Biochemistry, University of Houston, Houston, TX 77205-5001, USA.
Dryer
S E
SE
D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015151:Immunoblotting; D020890:Neuregulin-1 / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D018631:ras Proteins / Q000378:metabolism*
D020890:Neuregulin-1; D024681:Potassium Channels, Calcium-Activated; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C117467:neuregulin beta; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins