title: A rapid, nongenomic pathway facilitates the synaptic transmission induced by retinoic acid at the developing synapse.
abstract: We have previously shown that retinoic acid (RA), a factor highly expressed in spinal cord, rapidly and specifically enhances the spontaneous acetylcholine release at developing neuromuscular synapses in Xenopus cell culture, using whole-cell patch-clamp recording. We have now further investigated the underlying mechanisms that are involved in RA-induced facilitation on the frequency of spontaneous synaptic currents (SSCs). Buffering the rise of intracellular Ca2+ with BAPTA-AM hampered the facilitation of SSC frequency induced by RA. The prompt RA-enhanced SSC frequency was not abolished when Ca2+ was eliminated from the culture medium or there was bath application of the pharmacological Ca2+ channel inhibitor Cd2+, indicating that Ca2+ influx through voltage-activated Ca2+ channels are not required. Application of membrane-permeable inhibitors of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] or ryanodine receptors effectively blocked the increase of SSC frequency elicited by RA. Treating cells with either wortmannin or LY294002, two structurally different inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase) and with the phospholipase Cgamma (PLCgamma) inhibitor U73122, abolished RA-induced facilitation of synaptic transmission. Preincubation of the cultures with pharmacological inhibitors, either genistein, a broad-spectrum tyrosine kinase inhibitor, or PP2, which predominantly inhibits the Src family of nonreceptor tyrosine kinase, completely abolished RA-induced synaptic facilitation. Taken collectively, these results suggest that RA elicits Ca2+ release from Ins1,4,5P3 and/or ryanodine-sensitive intracellular Ca2+ stores of the presynaptic nerve terminal. This is done via PLCgamma/PI 3-kinase signaling cascades and Src tyrosine kinase activation, leading to an enhancement of spontaneous transmitter release.
authors.affiliation: Department of Biological Sciences, National Sun Yat-sen University, No. 70, Lein-Hai Rd., Kaohsiung City, 804, Taiwan.
authors.forename: Jau-Cheng
authors.initials: JC
authors.lastname: Liou
authors.forename: Shih-Yin
authors.initials: SY
authors.lastname: Ho
authors.forename: Meng-Ru
authors.initials: MR
authors.lastname: Shen
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Liao
authors.forename: Wen-Tai
authors.initials: WT
authors.lastname: Chiu
authors.forename: Kai-Hsiang
authors.initials: KH
authors.lastname: Kang
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005453:Fluorescence; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D004791:Enzyme Inhibitors; D014212:Tretinoin; D019869:Phosphatidylinositol 3-Kinases; D010738:Type C Phospholipases; D000109:Acetylcholine