Vascular endothelial growth factor (VEGF) signaling regulates hippocampal neurons by elevation of intracellular calcium and activation of calcium/calmodulin protein kinase II and mammalian target of rapamycin

Cell Signal. 2008 Apr;20(4):714-25. doi: 10.1016/j.cellsig.2007.12.009. Epub 2007 Dec 17.

Abstract

The present study was undertaken to characterize neuronal activity-dependent expression and release of vascular endothelial growth factor (VEGF) from rat hippocampal neurons and its contribution to neuronal functions. Increased levels of VEGF164 mRNA were evident both in cultured neurons and slices, but not astrocytes, following membrane depolarization with KCl. Activity-dependent expression of VEGF, as well as its release, was dependent on the activation of the N-methyl-d-aspartate receptors or L-type voltage-activated calcium channels. A brief (10 min) application of recombinant VEGF165 to neurons elicited a slow rise in cytosolic Ca2+ in a VEGFR2 dependent manner. The VEGF-induced Ca2+ responses required Ca2+ influx, phospholipase Cgamma and Ca2+ stores. An inhibitor of transient receptor potential canonical channels reduced the VEGF-induced Ca2+ responses by 50%, suggesting the involvement of transient receptor potential canonical channels in the VEGF-mediated responses. The same brief stimulus with VEGF led to long-term synaptic enhancement dependent on protein synthesis. VEGF had prominent effects on the activation calcium/calmodulin protein kinase II and cAMP responsive element binding protein as well as extracellular signal-regulated protein kinase and mammalian target of rapamycin-all in a VEGFR2 dependent manner. Our findings suggest that VEGF released from neuronal cells plays a local role in Ca2+ influx and synaptic transmission that may influence the generation of long-term changes in synaptic efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Calcium Channels, L-Type / metabolism
  • Calcium Signaling* / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hippocampus / drug effects
  • Hippocampus / embryology
  • Hippocampus / enzymology
  • Hippocampus / metabolism*
  • Membrane Potentials
  • Nerve Tissue Proteins / biosynthesis
  • Neuronal Plasticity*
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurons / metabolism*
  • Phospholipase C gamma / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Potassium Chloride / pharmacology
  • Protein Kinases / metabolism*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Recombinant Proteins / metabolism
  • Synaptic Transmission*
  • TOR Serine-Threonine Kinases
  • Time Factors
  • Transcription, Genetic
  • Transient Receptor Potential Channels / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Calcium Channels, L-Type
  • Carrier Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • Transient Receptor Potential Channels
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Potassium Chloride
  • Protein Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Vascular Endothelial Growth Factor Receptor-2
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Extracellular Signal-Regulated MAP Kinases
  • Phospholipase C gamma