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Extra- and Intracellular Sphingosylphosphorylcholine Promote Spontaneous Transmitter Release from Frog Motor Nerve Endings

Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee

Similar to phosphatidylinositol bisphosphate, sphingomyelin breakdown generates several lipids, including sphingosylphosphorylcholine (SPC), that are putative signaling molecules. The present study was undertaken to evaluate the involvement of SPC in transmitter release process. Intracellular recordings were made from isolated frog sciatic-sartorius nerve-muscle preparations, and the effects of SPC on neurosecretion in the form of miniature endplate potentials (MEPPs) were assessed. Extracellular application of SPC mixture (D,L-SPC) at 1, 10, and 25 µM increased the MEPP frequency by 68, 96, and 127%, respectively. D-erythro-SPC (dissolved in dimethyl sulfoxide but not coupled to bovine serum albumin), but not L-threo-SPC, was active extracellular; the former (at 10 µM) increased the MEPP frequency by 143%. D-erythro-SPC treatment did not significantly change the median amplitude or frequency-distribution of MEPPs. Intracellular delivery via liposomes, in which 10, 100, or 1000 µM SPC mixture was entrapped in liposomal aqueous phase, induced a concentration-dependent increase in MEPP frequency of 45, 91, and 100%, respectively. D-erythro-SPC and L-threo-SPC at the concentration of 100 µM increased the MEPP frequency by 117 and 67%, respectively, or 91 and 61%, respectively, when coupled to bovine serum albumin. Pretreatment with thapsigargin significantly reduced but did not abolish the effects of extracellular D-erythro-SPC (10 µM) or liposomes containing 100 µM D-erythro-SPC. Liposomes filled with 100 µM D-myo-inositol 1,4,5-trisphosphate (IP₃) enhanced the MEPP frequency to the same magnitude as 100 µM D-erythro-SPC entrapped in liposomes. However, administration of 100 µM D-erythro-SPC and IP₃ entrapped in the same liposomes enhanced the MEPP frequency by 70%, which was less than that produced by these two compounds alone. The result provides the first electrophysiological evidence that SPC can modulate transmitter release by an extra- or intracellular action at the frog motor nerve ending.

Address correspondence to: Nae J. Dun, Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, PO Box 70577, Johnson City, TN 37614-1708. E-mail: dunnae{at}etsu.edu