Neuronal expression of the human neuropeptide S receptor NPSR1 identifies NPS-induced calcium signaling pathways

PLoS One. 2015 Feb 25;10(2):e0117319. doi: 10.1371/journal.pone.0117319. eCollection 2015.


The neuropeptide S (NPS) system was discovered as a novel neurotransmitter system a decade ago and has since been identified as a key player in the modulation of fear and anxiety. Genetic variations of the human NPS receptor (NPSR1) have been associated with pathologies like panic disorders. However, details on the molecular fundamentals of NPSR1 activity in neurons remained elusive. We expressed NPSR1 in primary hippocampal cultures. Using single-cell calcium imaging we found that NPSR1 stimulation induced calcium mobilization from the endoplasmic reticulum via activation of IP3 and ryanodine receptors. Store-operated calcium channels were activated in a downstream process mediating entry of extracellular calcium. We provide the first detailed analysis of NPSR1 activity and the underlying intracellular pathways with respect to calcium mobilization in neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Calcium / metabolism
  • Calcium Signaling*
  • Cell Line
  • Endoplasmic Reticulum / metabolism
  • Gene Expression*
  • Gene Order
  • Genetic Vectors
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Mice
  • Models, Biological
  • Neurons / metabolism*
  • Neuropeptides / metabolism*
  • Pyramidal Cells / metabolism
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism


  • Inositol 1,4,5-Trisphosphate Receptors
  • NPSR1 protein, human
  • Neuropeptides
  • Receptors, G-Protein-Coupled
  • Ryanodine Receptor Calcium Release Channel
  • neuropeptide S, mouse
  • Calcium

Grant support

This work was supported by the Deutsche Forschungsgemeinschaft (SFB-TRR 58 TP A07 to K.J. and SFB-TRR 58 TP A03 to H.-C.P), the Max-Planck-Research Award (to H.-C.P.) and the Interdisziplinäres Zentrum für Klinische Forschung der Westfälischen Wilhelms-Universität Münster (IZKF, PaHC3/003/10 to H.-C.P. and K.J.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.