title: Natriuretic peptides block synaptic transmission by activating phosphodiesterase 2A and reducing presynaptic PKA activity.
abstract: 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.
authors.affiliation: Graduate School of Peking Union Medical College, Beijing 100730,  China.
authors.forename: Fei
authors.initials: F
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Ren
authors.forename: Ju-en
authors.initials: JE
authors.lastname: Zhang
authors.forename: Weixin
authors.initials: W
authors.lastname: Zhong
authors.forename: Minmin
authors.initials: M
authors.lastname: Luo
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D045265:Natriuretic Peptides / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000201:enzymology*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D045265:Natriuretic Peptides; D017868:Cyclic AMP-Dependent Protein Kinases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2