Inhibition of methyltransferase reduces the turnover of acetylcholine receptors.
Because of the putative rule of phospholipid methyltransferase reactions in many important membrane and receptor translocation processes, we studied the effect of methyltransferase inhibitors on acetylcholine receptor (AcChoR) turnover in cultured rat skeletal muscle. Inhibition of methyltransferase significantly reduced the normal rate of degradation of AcChoRs, a process that involves endocytosis. Further, under conditions that greatly accelerate the rate of degradation of AcChoRs--i.e., by addition of anti-AcChoR antibody--methyltransferase inhibitors again significantly reduced receptor turnover. AcChoR synthesis was unaffected. Thus, the net effect of this treatment was slowing of the antibody-induced loss of surface AcChoRs. That this drug effect was mediated specifically by inhibition of methylation reactions was suggested by certain additional pharmacologic features: partial reversibility of the effect by methionine, enhancement by homocysteine, and correspondence with marked inhibition of phospholipid methylation. The substrate specificity of the methyltransferase inhibitors capable of reducing AcChoR degradation suggests that phospholipid methylation reactions may be most relevant. Methyltransferase inhibitor drugs may provide a therapeutic strategy in receptor disorders such as myasthenia gravis, in which accelerated receptor endocytosis plays a major role.
Kuncl
R W
RW
Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD 21205.
Drachman
D B
DB
Adams
R
R
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology; D066298:In Vitro Techniques; D008715:Methionine / Q000494:pharmacology; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D009132:Muscles / Q000378:metabolism; D009157:Myasthenia Gravis / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000378:metabolism*
D010743:Phospholipids; D011978:Receptors, Nicotinic; D006710:Homocysteine; C010192:9-(2-hydroxy-3-nonyl)adenine; D008715:Methionine; D008780:Methyltransferases; D000225:Adenine; D000241:Adenosine; C006235:sinefungin