Intracellular signaling molecules involved in an inhibitory factor-induceddecrease in fetal-type AChR expression

The innervation-induced down-regulation of fetal-type acetylcholine recepto r (AChR) expression in developing muscle fibers has largely been attributed to nerve-evoked muscle activity; however, there is increasing evidence tha t a neural trophic factor also contributes to this receptor down-regulation . Previous studies from this laboratory have shown that neural extracts con tain a factor which decreases fetal-type AChR expression in skeletal muscle cell lines and therefore may account for the proposed inhibitory neurotrop hic influence. The current study investigated possible intracellular signal ing molecules involved in this receptor down-regulation and demonstrated th at activation of protein kinase C and p70(S6k) appeared to be important in receptor down-regulation. Decreases in AChR density were independent of myo genin. In addition, the receptor down-regulation was independent of neuregu lin, which also induces p70(S6k) activity. These studies demonstrate that n eural extracts contain an inhibitory factor which can down-regulate fetal-t ype AChR expression independently of nerve-evoked muscle activity through i ntracellular signaling molecules which are known to regulate AChR expressio n. (C) 2000 John Wiley & Sons, Inc.