Identification of the first biased NPS receptor agonist that retains anxiolytic and memory promoting effects with reduced levels of locomotor stimulation.
Identification of the first biased NPS receptor agonist that retains anxiolytic and memory promoting effects with reduced levels of locomotor stimulation.
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DOI：
10.1016/j.neuropharm.2017.03.001
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发表时间：
2017-05-15
影响因子：
4.7
通讯作者：
Runyon SP
中科院分区：
文献类型：
--
作者：
Clark SD;Kenakin TP;Gertz S;Hassler C;Gay EA;Langston TL;Reinscheid RK;Runyon SP
神经肽S系统与许多中枢调节的行为有关，包括巩固记忆、缓解焦虑和增加运动活动。这些行为的表征主要是使用内源性20AA肽(NPS)来完成的，它对人和啮齿动物NPS受体上的钙动员和cAMP第二信使通路具有相对相同的效力。这项研究首次证明，NPS肽的截短提供了仅在两个已知改变NPSR功能的单一多态变体(NPSR-107I)中的一个保持显著效力的小片段，但表明钙动员途径比cAMP途径有很大程度的偏向。我们还确定了截短肽的长度与钙动员途径的偏向程度有关。一种改进的四肽类似物(4)在体内大大减弱了过度运动刺激，但在与记忆巩固和抗焦虑活性相关的检测中保持了活性。类似物4在人和鼠的受体上也对钙动员途径有偏见。这表明，未来的NPS受体激动剂配体偏向于钙动员而不是cAMP产生，将作为非刺激性焦虑药物发挥作用，增强记忆形成。
The neuropeptide S system has been implicated in a number of centrally mediated behaviors including memory consolidation, anxiolysis, and increased locomotor activity. Characterization of these behaviors has been primarily accomplished using the endogenous 20AA peptide (NPS) that demonstrates relatively equal potency for the calcium mobilization and cAMP second messenger pathways at human and rodent NPS receptors. This study is the first to demonstrate that truncations of the NPS peptide provides small fragments that retain significant potency only at one of two single polymorphism variants known to alter NPSR function (NPSR-107I), yet demonstrate a strong level of bias for the calcium mobilization pathway over the cAMP pathway. We have also determined that the length of the truncated peptide correlates with the degree of bias for the calcium mobilization pathway. A modified tetrapeptide analog (4) has greatly attenuated hyperlocomotor stimulation in vivo but retains activity in assays that correlate with memory consolidation and anxiolytic activity. Analog 4 also has a bias for the calcium mobilization pathway, at the human and mouse receptor. This suggests that future agonist ligands for the NPS receptor having a bias for calcium mobilization over cAMP production will function as non-stimulatory anxiolytics that augment memory formation.