2012年10月8日,，北京生命科學(xué)研究所羅敏敏實(shí)驗(yàn)室在PNAS雜志上在線發(fā)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(jīng)遞質(zhì)傳遞的信號(hào)通路。
內(nèi)側(cè)韁核到腳間核的投射是腦內(nèi)主要的乙酰膽堿能通路,。從解剖學(xué)的角度來說,，這條通路是連接前腦邊緣系統(tǒng)和中腦調(diào)節(jié)系統(tǒng)的紐帶。從行為學(xué)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(lián)系,。在以前的研究中羅敏敏實(shí)驗(yàn)室首次報(bào)道了內(nèi)側(cè)韁核膽堿能神經(jīng)元可以同時(shí)釋放谷氨酸和乙酰膽堿兩種經(jīng)典的神經(jīng)遞質(zhì),，而且這兩種神經(jīng)遞質(zhì)引起的突觸后神經(jīng)元反應(yīng)是不同的。在本研究中,，我們利用光遺傳學(xué)刺激和電生理記錄相結(jié)合的方法發(fā)現(xiàn)心臟多肽激素心房利鈉肽能阻斷內(nèi)側(cè)韁核神經(jīng)元釋放谷氨酸,。藥理學(xué)的分析表明這種阻斷作用是磷酸二酯酶2A介導(dǎo)的，而和環(huán)磷酸鳥苷激活的蛋白激酶G或是環(huán)磷酸鳥苷敏感的CNG通道都沒有關(guān)系,。另外,，往腳間核處注入心房利鈉肽可以增強(qiáng)“壓力誘導(dǎo)的鎮(zhèn)痛”作用，這種增強(qiáng)效應(yīng)可以被磷酸二酯酶2A的抑制劑所消除,。磷酸二酯酶2A在內(nèi)側(cè)韁核神經(jīng)元的軸突末梢高表達(dá),，其受到環(huán)磷酸鳥苷激活后，可以降解本底水平的環(huán)磷酸腺苷,。特異性的激活蛋白激酶A可以完全反轉(zhuǎn)心房利鈉肽對(duì)谷氨酸釋放的抑制作用,。這些結(jié)果說明了心房利鈉肽在腦內(nèi)具有很強(qiáng)的突觸前抑制作用，同時(shí)磷酸二酯酶2A可以通過負(fù)調(diào)控環(huán)磷酸鳥苷和環(huán)磷酸腺苷這兩條相關(guān)聯(lián)的信號(hào)通路來調(diào)節(jié)神經(jīng)遞質(zhì)釋放從而在生理學(xué)和行為學(xué)方面起到重要作用,。
利鈉肽及其受體在腦內(nèi)廣泛的表達(dá),，但它們的生理學(xué)功能及其傳導(dǎo)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(jīng)遞質(zhì)傳遞的信號(hào)通路,。在傳統(tǒng)觀念里,，環(huán)磷酸鳥苷對(duì)突觸傳遞的調(diào)節(jié)主要是由蛋白激酶G介導(dǎo)的。但是無論是我們電生理的數(shù)據(jù)還是生化數(shù)據(jù)都表明磷酸二酯酶2A介導(dǎo)了心房利鈉肽的突觸前抑制作用,。因此這項(xiàng)工作首次揭示了腦內(nèi)環(huán)磷酸鳥苷信號(hào)與環(huán)磷酸腺苷通路的聯(lián)系,。也驗(yàn)證了中樞神經(jīng)系統(tǒng)與外周心血管系統(tǒng)在某些調(diào)控方式中的共同性。另外,，多年的研究表明蛋白激酶A對(duì)于突觸傳遞是很重要的,。我們的實(shí)驗(yàn)從電生理的角度為這一觀點(diǎn)給出了最直接有力的證據(jù)。（生物谷Bioon.com）
doi: 10.1073/pnas.1209185109
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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.
