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- Title
Regulation of NLGN3 and the Synaptic Rho-GEF Signaling Pathway by CDK5.
- Authors
Jaehoon Jeong; Wenyan Han; Eunhye Hong; Pandey, Saurabh; Yan Li; Wei Lu; Roche, Katherine W.
- Abstract
Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that are involved in synapse assembly and function. The NLGN gene family consists of 5 genes (NLGN1-3, 4X, and 4Y). NLGN3 forms heterodimers with other NLGNs and is expressed at both excitatory and inhibitory synapses, although the distinct role at different synapses is not fully understood. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that targets various neuronal substrates to impact neuronal migration, neurite outgrowth, synaptic transmission, and plasticity. Both NLGNs and their presynaptic binding partners neurexins are highly associated with neurodevelopmental disorders. The NLGN3 gene is on the X chromosome and variants in NLGN3 have been linked to the pathophysiology in neurodevelopmental disorders. To better understand the endogenous modulation of NLGN3, we generated an HA-tagged knock-in mouse. We found that Cdk5 associates with NLGN3 in vivo and phosphorylates NLGN3 on serine 725 (S725) in the knock-in mouse of either sex. The phosphorylation affects the NLGN3 association with Kalirin-7, a postsynaptic guanine nucleotide exchange factors for Rho GTPase family proteins. We further observed that the phosphorylation modulates NLGN3 surface expression and NLGN3-mediated synaptic currents in cultured rat neurons. Thus, we characterized NLGN3 as a novel Cdk5 substrate and revealed the functional consequences of NLGN3 S725 phosphorylation in neurons. Our study provides a novel molecular mechanism underlying Cdk5-mediated regulation of postsynaptic cell adhesion molecules.
- Subjects
GUANINE nucleotide exchange factors; CELL adhesion; CELLULAR signal transduction; RHO factor; NEURAL transmission; X chromosome; CELL adhesion molecules
- Publication
Journal of Neuroscience, 2023, Vol 43, Issue 44, p7264
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2309-22.2023