Abstract
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.
Highlights
In 2004, the 20 amino acid neuropeptide S (NPS) has been identified as the ligand for the formerly orphan g-protein coupled receptor GPR-154 ( NPS receptor, NPSR1) [1], with NPS/ NPSR1 forming a novel neurotransmitter system in the brain [2]
In a first set of experiments we developed a protocol for the functional expression of NPSR1 in cultured mouse hippocampus neurons
NPSR1 was neither detectable in the plasma membrane nor in the intracellular fraction prepared from untransfected controls
Summary
In 2004, the 20 amino acid neuropeptide S (NPS) has been identified as the ligand for the formerly orphan g-protein coupled receptor GPR-154 ( NPS receptor, NPSR1) [1], with NPS/ NPSR1 forming a novel neurotransmitter system in the brain [2]. Human studies have linked the NPS system and singlenucleotide polymorphisms in the NPSR1 gene to diseases like asthma and allergy [15,16], inflammatory bowel disease [17], rheumatoid arthritis [18] and panic disorders [19,20,21,22]. Despite these numerous biological functions, little is known about the molecular mechanisms underlying NPS receptor activity.
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