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p21-activated kinase 1 restricts tonic endocannabinoid signaling in the hippocampus.

By June 14, 2016No Comments
2016 Jun 14;5. pii: e14653. doi: 10.7554/eLife.14653.
Xia S1, Zhou Z1,2, Leung C3,4, Zhu Y1, Pan X1, Qi J1, Morena M5,6, Hill MN5,6, Xie W1,2, Jia Z3,4.

Abstract

PM 1aPAK1 inhibitors are known to markedly improve social and cognitive function in several animal models of brain disorders, including autism, but the underlying mechanisms remain elusive. 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.

KEYWORDS:

AEA; COX-2; GABA transmission; P21-activated kinase; cannabinoid signaling; mouse; neuroscience

PMID: 27296803

 

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