Orphan G Protein-Coupled Receptors and Novel Neuropeptides

Rainer K. Reinscheid, Reinscheid, Rainer K.

Neuropeptide S (NPS) is one of the most recent examples of a neurotransmitter identified by the orphan receptor strategy. Impressive progress has been made in the short time since its identification to determine physiological functions modulated by NPS. The anatomical distribution of NPS and its receptor, NPSR, suggests possible functions in the regulation of vigilance states and modulation of emotional behaviors. Early studies provided evidence that NPS induces behavioral arousal and promotes wakefulness by suppressing all stages of sleep. NPS was also found to produce anxiolytic-like effects in behavioral paradigms that measure fear or responses to novelty. Recent studies have demonstrated that NPS can modulate energy and endocrine homeostasis. Differential regulation of NPS and NPSR transcripts was observed after caffeine or nicotine treatment, indicating complex interactions with adenosine and cholinergic systems. NPS has been found co-localized with other excitatory transmitters such as glutamate, acetylcholine, or corticotropine-releasing factor. Activation of NPSR triggers mobilization of intracellular Ca2+ and stimulation of cAMP synthesis, therefore increasing cellular excitability. A functional polymorphism in NPSR has been identified that produces a gain-of-function phenotype by increasing agonist potency up to tenfold. Finally, a gender-specific association of this NPSR polymorphism with panic disorder was found in male patients, indicating that the NPS system might be involved in modulating anxiety responses in humans. Further studies about interactions of the NPS system with other transmitter systems might help to discover additional functions of NPS and define its role within complex neural networks.