| Annotated protein: | Serine/threonine-protein kinase PAK 1 (EC 2.7.11.1) (Alpha-PAK) (CDC42/RAC effector kinase PAK-A) (p21-activated kinase 1) (PAK-1) (p65-PAK). Gene symbol: PAK1. Taxonomy: Mus musculus (Mouse). Uniprot ID: O88643 |
| antibody wiki: | |
| SynGO gene info: | SynGO data @ PAK1 |
| Ontology domain: | Biological Process |
| SynGO term: | regulation of trans-synaptic signaling by endocannabinoid, modulating synaptic transmission (GO:0150036) |
| Synapse type(s): | hippocampus, GABAergic |
| Annotated paper: | Xia S, et al. "p21-activated kinase 1 restricts tonic endocannabinoid signaling in the hippocampus" Elife. 2016 Jun 14;5:e14653 PMID:27296803 |
| Figure(s): | Fig1,2,3,6 with support of the other figures |
| Annotation description: | Postsynaptic PAK1 stimulates presynaptic GABA release by inhibiting negative feedback of endocannabinoids. Fig1: PAK1 null has impaired E/I balance (Fig1C), mainly through impaired IPSC input on CA1 pyramidal neurons, which is also mimicked by PAK1 inhibitor or microdialysis of inhibiting peptide in the pyramidal neuron (post synaptic 1F). Fig 2 and 3 show that mIPSC frequency is impaired in the PAK1 null or PAK inhibitor, amplitude is normal. mEPSCs are also normal, indicating that presynaptic GABA release is selectively impaired. This is verified in Fig4G that shows a GABA puff on cultured PAK1 null neurons gives a normal postsynaptic response. Fig 6 shows that blocking postsynaptic PAK1 by KO, inhibitor or peptide these all enhance CB1 antagonist effect, indicating enhanced endocannabinoid signalling in absence of postsynaptic PAK1 leads to a reduction of presynaptic GABA release. This enhancement of the CB1 antagonist is phenocopied by COX-2 inhibition in WT cells, and no further enhancement is observed in the PAK1 null (Fig8B) indicating that PAK1 inhibits retrograde endocannabinoid signalling through COX-2. In line with this, less COX-2 is observed in synapses of PAK1 null mice (Fig7K, 9M). |
| Evidence tracking, Biological System: | Intact tissue Cultured neurons |
| Evidence tracking, Protein Targeting: | Genetic transformation (eg; knockout, knockin, mutations) Antagonist / agonist |
| Evidence tracking, Experiment Assay: | Confocal Whole-cell patch clamp Western blot Biochemical fractionation (generic) |
| Annotator(s): | Jan van Weering (ORCID:0000-0001-5259-4945) Matthijs Verhage (ORCID:0000-0002-2514-0216) |
| Lab: | Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands |
| SynGO annotation ID: | 2392 |
| Dataset release (version): | 20231201 |
| View annotation as GO-CAM model: |  |