Developmental regulation of neuronal KCa channels by TGFβ1:: Transcriptional and posttranscriptional effects mediated by Erk MAP kinase

An avian ortholog of transforming growth factor beta 1 (TGF beta 1) is the target-derived factor responsible for the developmental expression of large-conductance Ca2+-activated K+ (K-Ca) channels in chick ciliary ganglion (CG) neurons developing in vivo and in vitro. Application of TGF beta 1 evokes an acute stimulation of K-Ca that can be observed immediately after cessation of a 12 hr exposure to this factor, that persists in the presence of protein synthesis inhibitors, and that is therefore mediated by posttranslational events. Here we show that a single 3 hr exposure to TGF beta 1 can also induce long-lasting stimulation of macroscopic K-Ca that persists for at least 3.5 d after the end of the treatment. In contrast to the acute stimulation, this sustained effect is dependent on the transcription and synthesis of new proteins at approximately the time of TGF beta 1 treatment. However TGF beta 1 does not cause increases in the levels of slowpoke a subunit transcripts in CG neurons, suggesting that induction of some other protein or proteins is required for sustained enhancement of macroscopic K-Ca. In addition, application of TGF beta 1 evoked an almost immediate but transient phosphorylation of the mitogen-activated protein kinase Erk in CG neurons. TGF beta 1-evoked Erk activation was blocked by the specific MEK1 inhibitor 2-(2'- amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059). Moreover, application of PD98059 blocked both acute and sustained K-Ca stimulation evoked by TGF beta 1. These results indicate that TGF beta 1 elicits a biphasic stimulation of K-Ca via activation of an MEK1-Erk pathway and raise the possibility that other neuronal effects of TGF beta superfamily members entail Erk activation.