Graduate School of Peking Union Medical College, Beijing 100730, China.
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17681-6. doi: 10.1073/pnas.1209185109. Epub 2012 Oct 8.
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.
心肽激素心房利钠肽（ANP）通过刺激鸟苷酸环化酶-A 产生环鸟苷酸（cGMP）来调节血压。ANP 和鸟苷酸环化酶-A 也在许多脑区表达，但它们的生理功能和下游信号通路仍然是个谜。在这里，我们研究了 ANP 信号在从中脑内侧缰核（MHb）到脚间核（IPN）的神经通路上的生理功能。生化测定表明，ANP 增加了小鼠脑切片中 IPN 中的 cGMP 积累。通过光遗传学刺激和电生理记录，我们表明 ANP 和脑利钠肽均可显著阻断 MHb 神经元的谷氨酸释放。药理学应用表明，这种阻断是由磷酸二酯酶 2A（PDE2A）介导的，而不是由 cGMP 刺激的蛋白激酶-G 或 cGMP 敏感的环核苷酸门控通道介导的。此外，将 ANP 聚焦注入 IPN 可增强应激诱导的镇痛，而 PDE2A 抑制剂可阻止增强作用。PDE2A 在 MHb 神经元的轴突末梢中丰富表达，其被 cGMP 激活可耗尽环腺苷单磷酸。ANP 对谷氨酸释放的抑制作用可通过选择性激活蛋白激酶 A 逆转。这些结果表明，脑内利钠肽具有很强的突触前抑制作用，并表明 PDE2A 在通过 cGMP 信号通路和环腺苷单磷酸信号通路的负交叉对话调节神经递质释放方面具有重要的生理和行为作用。
