2012年10月8日，北京生命科學研究所羅敏敏實驗室在PNAS雜誌上在線發表題為Natriuretic peptides block synaptic transmission by activating phosphodiesterase 2A and reducing presynaptic PKA activity的文章。該文闡明了迄今為止最完整的心臟多肽激素心房利鈉肽抑制突觸前神經遞質傳遞的信號通路。
內側韁核到腳間核的投射是腦內主要的乙醯膽鹼能通路。從解剖學的角度來說，這條通路是連接前腦邊緣系統和中腦調節系統的紐帶。從行為學的角度來說，該通路與睡眠，壓力，痛以及尼古丁上癮等行為都有著聯繫。在以前的研究中羅敏敏實驗室首次報導了內側韁核膽鹼能神經元可以同時釋放穀氨酸和乙醯膽鹼兩種經典的神經遞質，而且這兩種神經遞質引起的突觸後神經元反應是不同的。在本研究中，我們利用光遺傳學刺激和電生理記錄相結合的方法發現心臟多肽激素心房利鈉肽能阻斷內側韁核神經元釋放穀氨酸。藥理學的分析表明這種阻斷作用是磷酸二酯酶2A介導的，而和環磷酸鳥苷激活的蛋白激酶G或是環磷酸鳥苷敏感的CNG通道都沒有關係。另外，往腳間核處注入心房利鈉肽可以增強「壓力誘導的鎮痛」作用，這種增強效應可以被磷酸二酯酶2A的抑制劑所消除。磷酸二酯酶2A在內側韁核神經元的軸突末梢高表達，其受到環磷酸鳥苷激活後，可以降解本底水平的環磷酸腺苷。特異性的激活蛋白激酶A可以完全反轉心房利鈉肽對穀氨酸釋放的抑制作用。這些結果說明了心房利鈉肽在腦內具有很強的突觸前抑制作用，同時磷酸二酯酶2A可以通過負調控環磷酸鳥苷和環磷酸腺苷這兩條相關聯的信號通路來調節神經遞質釋放從而在生理學和行為學方面起到重要作用。
利鈉肽及其受體在腦內廣泛的表達，但它們的生理學功能及其傳導通路研究得卻不是很清楚。我們的工作闡明了迄今為止最完整的心房利鈉肽抑制突觸前神經遞質傳遞的信號通路。在傳統觀念裡，環磷酸鳥苷對突觸傳遞的調節主要是由蛋白激酶G介導的。但是無論是我們電生理的數據還是生化數據都表明磷酸二酯酶2A介導了心房利鈉肽的突觸前抑制作用。因此這項工作首次揭示了腦內環磷酸鳥苷信號與環磷酸腺苷通路的聯繫。也驗證了中樞神經系統與外周心血管系統在某些調控方式中的共同性。另外，多年的研究表明蛋白激酶A對於突觸傳遞是很重要的。我們的實驗從電生理的角度為這一觀點給出了最直接有力的證據。（生物谷Bioon.com）
Natriuretic peptides block synaptic transmission by activating phosphodiesterase 2A and reducing presynaptic PKA activity
Fei Hu, Jing Ren, Ju-en Zhang, Weixin Zhong, and Minmin Luo
The heart peptide hormone atrial natriuretic peptide (ANP) regulates blood pressure by stimulating guanylyl cyclase-A to produce cyclic guanosine monophosphate (cGMP). ANP and guanylyl cyclase-A are also expressed in many brain areas, but their physiological functions and downstream signaling pathways remain enigmatic. Here we investigated the physiological functions of ANP signaling in the neural pathway from the medial habenula (MHb) to the interpeduncular nucleus (IPN). Biochemical assays indicate that ANP increases cGMP accumulation in the IPN of mouse brain slices. Using optogenetic stimulation and electrophysiological recordings, we show that both ANP and brain natriuretic peptide profoundly block glutamate release from MHb neurons. Pharmacological applications reveal that this blockade is mediated by phosphodiesterase 2A (PDE2A) but not by cGMP-stimulated protein kinase-G or cGMP-sensitive cyclic nucleotide-gated channels. In addition, focal infusion of ANP into the IPN enhances stress-induced analgesia, and the enhancement is prevented by PDE2A inhibitors. PDE2A is richly expressed in the axonal terminals of MHb neurons, and its activation by cGMP depletes cyclic adenosine monophosphates. The inhibitory effect of ANP on glutamate release is reversed by selectively activating protein kinase A. These results demonstrate strong presynaptic inhibition by natriuretic peptides in the brain and suggest important physiological and behavioral roles of PDE2A in modulating neurotransmitter release by negative crosstalk between cGMP-signaling and cyclic adenosine monophosphate-signaling pathways.