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We show here that disruption of PAK1 in mice suppresses inhibitory neurotransmission through an increase in tonic, but not phasic, secretion of endocannabinoids (eCB). Consistently, we found elevated levels of anandamide (AEA), but not 2-arachidonoylglycerol (2-AG) following PAK1 disruption. This increased tonic AEA signaling is mediated by reduced cyclooxygenase-2 (COX-2), and COX-2 inhibitors recapitulate the effect of PAK1 deletion on GABAergic transmission in a CB1 receptor-dependent manner. These results establish a novel signaling process whereby PAK1 upregulates COX-2, reduces AEA and restricts tonic eCB-mediated processes. Because PAK1 and eCB are both critically involved in many other organ systems in addition to the brain, our findings may provide a unified mechanism by which PAK1 regulates these systems and their dysfunctions including cancers, inflammations and allergies.<\/jats:p>","DOI":"10.7554\/elife.14653","type":"journal-article","created":{"date-parts":[[2016,6,14]],"date-time":"2016-06-14T01:14:13Z","timestamp":1465866853000},"source":"Crossref","is-referenced-by-count":20,"title":["p21-activated kinase 1 restricts tonic endocannabinoid signaling in the hippocampus"],"prefix":"10.7554","volume":"5","author":[{"given":"Shuting","family":"Xia","sequence":"first","affiliation":[{"name":"The Key Laboratory of Developmental Genes and Human Disease, Jiangsu Co-innovation Center of Neuroregeneration, Southeast University, Nanjing, 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