Benzodiazepine and β-adrenergic receptor ligands independently stimulate phospholipid methylation

Abstract

The stepwise methylation of phosphatidylethanolamine by two methyltransferase synthesises phosphatidylcholine in membranes¹. Although the CDP-choline pathway is the major route for phosphatidylcholine synthesis, recent work in our laboratory has found that the methylation pathway is metabolically highly active. The phospholipid methyltransferases, their substrates and their products are asymmetrically distributed in the cell membrane. Methyltransferase I, located on the cytoplasmic side of the membrane, transfers a methyl group from S-adenosylmethionine to phosphatidylethanolamine to form phosphatidyl-N-monomethylethanolamine. Methyltransferase II, on the exterior surface of the bilayer, catalyses two additional N-methylations to form phosphatidylcholine. The asymmetric distribution of methyltransferases results in the synthesis and translocation of phosphatidylcholine to the exterior bilayer surface². The synthesis and translocation of methylated phos-pholipid affects many membrane events, such as fluidity³, coupling of the β-adrenergic receptor with adenylate cyclase⁴, the number of β-adrenergic receptors⁵, Ca²⁺-ATPase activity⁶, leukocyte chemotaxis⁷, mast cell histamine secretion⁸ and lymphocyte mitogenesis⁹. We now report that stimulation of a benzodiazepine receptor with anti-anxiety benzodiazepines, and stimulation of the β-adrenergic receptor with β-agonists, increase phospholipid methylation in C₆ astrocytoma cells. Furthermore, simultaneous addition of benzodiazepine and β-adrenergic agonists increases methylation in an additive manner.