p21-activated kinase 1 restricts tonic endocannabinoid signaling in the hippocampus
Open accessAbstract
PAK1 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.
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P21-associated kinase enhances tonic AEA signaling at hippocampal GABAergic synapses by reducing synaptic COX-2 levels and subsequent decreases in COX-2-mediated inactivation of AEA signaling.
“recent work has also demonstrated P21-associated kinase enhances tonic AEA signaling at hippocampal GABAergic synapses by reducing synaptic COX-2 levels and subsequent decreases in COX-2-mediated inactivation of AEA signaling (Xia et al., 2016).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Xia et al., 2016
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- Authors
- Xia, S., Zhou, Z., Leung, C., Zhu, Y., Pan, X., Qi, J., Morena, M., Hill, M. N., Xie, W., & Jia, Z.
- Affiliations
- Southeast University (CN)
- University of Toronto (CA)
- University of Calgary (CA)
- Corresponding author
- Hill, Matthew N
- Xie, Wei
- Jia, Zhengping
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-06-14
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4907698
- OpenAlex
- W2422184525
- Cited by
- 21
- References
- 49
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 6 · 2016: 1
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Natural Science Foundation of China (31571040)
- Canadian Institutes of Health Research (MOP119421)
- The China National Basic Research Program (2012CB517903)
- Natural Sciences and Engineering Research Council of Canada (RGPIN341498)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- PAK1, endocannabinoid signaling, tonic inhibition, anandamide, cyclooxygenase-2, GABAergic neurotransmission, CB1 receptor, hippocampus, inhibitory neurotransmission, autism spectrum disorder, COX-2 inhibitors
- MeSH terms
- Animals, Hippocampus, Mice, Knockout, Mice, Cyclooxygenase 2, p21-Activated Kinases, Endocannabinoids
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