title: Activation of UTP-sensitive P2Y2 receptor induces the expression of cholinergic genes in cultured cortical neurons: a signaling cascade triggered by Ca2+ mobilization and extracellular regulated kinase phosphorylation.
abstract: ATP functions as an extracellular signaling molecule that is costored and coreleased with neurotransmitters at central and peripheral neuronal synapses. Stimulation by ATP upregulates the expression of synaptic genes in muscle-including the genes for nicotine acetylcholine receptor (α-, δ-, and ε-subunits) and acetylcholinesterase (AChE)-via the P2Y receptor (P2YR), but the trophic response of neurons to the activation of P2YRs is less well understood. We reported that cultured cortical neurons and the developing rat brain expressed different types of P2YRs, and among these the UTP-sensitive P2Y2R was the most abundant. P2Y2R was found to exist in membrane rafts and it colocalized with the postsynaptic protein PSD-95 in cortical neurons. Notably, agonist-dependent stimulation of P2Y2R elevated the neuronal expression of cholinergic genes encoding AChE, PRiMA (an anchor for the globular form AChE), and choline acetyltransferase, and this induction was mediated by a signaling cascade that involved Ca(2+) mobilization and extracellular regulated kinases 1/2 activation. The importance of P2Y2R action was further shown by the receptor's synergistic effect with P2Y1R in enhancing cholinergic gene expression via the robust stimulation of Ca(2+) influx. Taken together our results revealed a developmental function of P2Y2R in promoting synaptic gene expression and demonstrated the influence of costimulation of P2Y1R and P2Y2R in neurons.
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China. roychoi@ust.hk.
authors.forename: Roy C Y
authors.initials: RC
authors.lastname: Choi
authors.forename: Glanice K Y
authors.initials: GK
authors.lastname: Chu
authors.forename: Nina L
authors.initials: NL
authors.lastname: Siow
authors.forename: Amanda W Y
authors.initials: AW
authors.lastname: Yung
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Yung
authors.forename: Pinky S C
authors.initials: PS
authors.lastname: Lee
authors.forename: Christopher C W
authors.initials: CC
authors.lastname: Lo
authors.forename: Joseph
authors.initials: J
authors.lastname: Simon
authors.forename: Tina T X
authors.initials: TT
authors.lastname: Dong
authors.forename: Eric A
authors.initials: EA
authors.lastname: Barnard
authors.forename: Karl W K
authors.initials: KW
authors.lastname: Tsim
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058472:Receptors, Purinergic P2Y1 / Q000235:genetics / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014544:Uridine Triphosphate / Q000378:metabolism*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508016:PRiMA1 protein, rat; D058912:Purinergic P2Y Receptor Agonists; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; C548246:Ache protein, rat; D002118:Calcium; D014544:Uridine Triphosphate