Developmental regulation of neuronal KCa channels by TGFbeta 1: transcriptional and posttranscriptional effects mediated by Erk MAP kinase.
An avian ortholog of transforming growth factor beta1 (TGFbeta1) is the target-derived factor responsible for the developmental expression of large-conductance Ca(2+)-activated K(+) (K(Ca)) channels in chick ciliary ganglion (CG) neurons developing in vivo and in vitro. Application of TGFbeta1 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 TGFbeta1 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 TGFbeta1 treatment. However TGFbeta1 does not cause increases in the levels of slowpoke alpha 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 TGFbeta1 evoked an almost immediate but transient phosphorylation of the mitogen-activated protein kinase Erk in CG neurons. TGFbeta1-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 TGFbeta1. These results indicate that TGFbeta1 elicits a biphasic stimulation of K(Ca) via activation of an MEK1-Erk pathway and raise the possibility that other neuronal effects of TGFbeta superfamily members entail Erk activation.
Lhuillier
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Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5513, USA.
Dryer
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005726:Ganglia, Parasympathetic / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics*; D024681:Potassium Channels, Calcium-Activated; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one