title: Learning-related synaptic growth mediated by internalization of Aplysia cell adhesion molecule is controlled by membrane phosphatidylinositol 4,5-bisphosphate synthetic pathway.
abstract: Long-term facilitation in Aplysia is accompanied by the growth of new synaptic connections between the sensory and motor neurons of the gill-withdrawal reflex. One of the initial steps leading to the growth of these synapses is the internalization, induced by 5-HT, of the transmembrane isoform of Aplysia cell-adhesion molecule (TM-apCAM) from the plasma membrane of sensory neurons (Bailey et al., 1992). However, the mechanisms that govern the internalization of TM-apCAM and how this internalization is coupled to the molecular events that initiate the structural changes are not fully understood. Here, we report that the synthesis of membrane phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], which is known to be mediated by a signaling cascade through Aplysia Sec7 protein (ApSec7) and phosphatidylinositol-4-phosphate 5-kinase type I α (PIP5KIα) is required for both the internalization of TM-apCAM and the initiation of synaptic growth during 5-HT-induced long-term facilitation. Pharmacological blockade of PI(4,5)P(2) synthesis by the application of the inhibitor phenylarsine oxide blocked the internalization of apCAM. Furthermore, perturbation of the endogenous activation of ApSec7 and its downstream target PIP5KIα also blocked 5-HT-mediated internalization of TM-apCAM and synaptic growth. Finally, long-term facilitation was specifically impaired by blocking the ApSec7 signaling pathway at sensory-to-motor neuron synapses. These data indicate that the ApSec7/PIP5KIα signaling pathway is actively recruited during learning-related 5-HT signaling and acts as a key regulator of apCAM internalization associated with the formation of new synaptic connections during long-term facilitation.
authors.affiliation: National Creative Research Initiative Center for Memory, Department of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanak-gu, Seoul 151-747, Korea.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Jaehoon
authors.initials: J
authors.lastname: Shim
authors.forename: Sun-Lim
authors.initials: SL
authors.lastname: Choi
authors.forename: Nuribalhae
authors.initials: N
authors.lastname: Lee
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Lee
authors.forename: Craig H
authors.initials: CH
authors.lastname: Bailey
authors.forename: Eric R
authors.initials: ER
authors.lastname: Kandel
authors.forename: Deok-Jin
authors.initials: DJ
authors.lastname: Jang
authors.forename: Bong-Kiun
authors.initials: BK
authors.lastname: Kaang
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001048:Aplysia / Q000502:physiology*; D053898:Biosynthetic Pathways / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D003001:Cloning, Molecular; D018920:Coculture Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D007150:Immunohistochemistry; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D008845:Microinjections; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000502:physiology; D016501:Neurites / Q000502:physiology; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000096:biosynthesis* / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology*
chemical_list: D015815:Cell Adhesion Molecules; D020662:Guanine Nucleotide Exchange Factors; D019269:Phosphatidylinositol 4,5-Diphosphate; C066755:Sec7 guanine nucleotide exchange factors; D012701:Serotonin; D019870:1-Phosphatidylinositol 4-Kinase