Synaptic NMDA-type glutamate receptors (NMDARs) are central components of all neural computations. NMDAR levels critically vary between synapses but how the synaptic localization of NMDARs is controlled remains unclear. Here we show that SIK3, a serine–threonine protein kinase, localizes to synapses where it phosphorylates the obligatory NMDAR subunit GluN1 at a single site.
This single phosphorylation event controls NMDAR recruitment to synapses. Genetic deletion of SIK3 severely and selectively decreases synaptic GluN1 levels by ~60% without altering AMPA-type glutamate receptor levels or inducing major transcriptional changes. Pharmacological inhibition of SIK3 impairs synaptic NMDAR responses within 45 minutes.
Mutating the SIK3-phosphorylation site inhibits GluN1 synaptic recruitment. Thus, SIK3 phosphorylation of GluN1 provides a key signal for recruiting NMDARs to synapses. This is a preview of subscription content, access via your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription Receive 12 print issues and online access Prices may be subject to local taxes which are calculated during checkout All raw data used for this study have been deposited in the Stanford Data Repository and are available at https://purl.stanford.edu/yn049vf6243.
The RNA-seq data were archived in the GEO database (GSE278753). Source data are provided with this paper. Structure, function, and allosteric modulation of NMDA receptors.
Physiol. 150, 1081–1105 (2018). Article PubMed PubMed Central CAS Google Scholar Mony, L. & Paoletti, P. Mechanisms of NMDA receptor regulation.
Neurobiol. 83, 102815 (2023). P., Nicole, O. & Groc, L. NMDA receptor functions in health and disease: old actor, new dimensions.
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