The p38 mitogen-activated protein kinase pathway negatively regulates Ca2+-activated K+ channel trafficking in developing parasympathetic neurons

The trafficking of large-conductance Ca2+-activated K+ channels (K-Ca) in chick ciliary ganglion neurons is regulated by growth factors. Here we show that a canonical p38 cascade inhibits K-Ca trafficking in ciliary ganglion neurons. Two different p38 inhibitors (SB202190 or SB203580) or over-expression of dominant-negative forms of several components of the p38 cascade increased K-Ca in ciliary neurons. Inhibition of protein synthesis or Golgi processing had no effect on this phenomenon, suggesting that p38 is acting at a distal step of the trafficking pathway. Depolymerization of filamentous actin (F-actin) increased functional expression of K-Ca, whereas stabilization of F-actin inhibited the effect of SB202190 on K-Ca trafficking. SB202190 also caused an immunochemically detectable increase in K-Ca on the plasma membrane. Inhibition of p38 decreased the extent of cortical F-actin in ciliary neurons. Macroscopic K-Ca is suppressed by transforming growth factor (TGF) beta 3. Application of TGF beta 3 increased the phosphorylation of p38 in ciliary neurons and increased cortical F-actin. Thus, the p38 signaling cascade endogenously suppresses development of functional K-Ca, in part by stabilizing an F-actin barrier that prevents plasma membrane insertion of functional channel complexes. This cascade also appears to mediate inhibitory effects of TGF beta 3 on the expression of K-Ca.