Downregulation and increased turnover of beta-amyloid precursor protein in skeletal muscle cultures by neuregulin-1.
The beta-amyloid precursor protein (betaAPP) is found in skeletal muscle localized to the base of the postsynaptic folds of the neuromuscular junction; yet here, as well as in neurons, its function remains enigmatic. Here we report that the motor nerve-derived trophic factor neuregulin-1 (NRG1) regulates both steady-state betaAPP levels as well as the metabolism of the cell surface-associated protein in cultured muscle cells. These two effects occur over two discernible time scales. At short times (minutes to hours), NRG1 increases the rate of internalization and apparent degradation of cell surface betaAPP while reducing the release of soluble APP to the medium. At longer times (hours to days), NRG1 causes a decrease in mRNA for betaAPP with a concomitant reduction in steady-state protein levels. These are novel findings for this trophic factor originally identified as inducing the expression of nicotinic acetylcholine receptors and other important synaptic proteins in skeletal muscle. They suggest that betaAPP may play a receptor or signal transduction role at the neuromuscular junction since other receptor protein's actions are terminated in a similar fashion. The effects of NRG1 on betaAPP metabolism are overcome by inhibitors of both the phosphatidylinositol-3 (PI3) kinase and mitogen-activated protein (MAP) kinase pathways, yet are distinct from those activated during induction of nicotinic acetylcholine receptor biosynthesis. BetaAPP should be added to the list of specialized post-neuromuscular junction proteins that are regulated by cholinergic terminal-derived factors critical to synaptogenesis.
Rosen
Kenneth M
KM
Division of Neurology, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. Kenneth_Rosen@cchcs.org
Ford
Byron D
BD
Querfurth
Henry W
HW
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020890:Neuregulin-1 / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D020890:Neuregulin-1; D012333:RNA, Messenger