An evolutionary switch in ND2 enables Src kinase regulation of NMDA receptors

Abstract

The non-receptor tyrosine kinase Src is a key signalling hub for upregulating the function of N-methyl D-aspartate receptors (NMDARs). Src is anchored within the NMDAR complex via NADH dehydrogenase subunit 2 (ND2), a mitochondrially encoded adaptor protein. The interacting regions between Src and ND2 have been broadly identified, but the interaction between ND2 and the NMDAR has remained elusive. Here we generate a homology model of ND2 and dock it onto the NMDAR via the transmembrane domain of GluN1. This interaction is enabled by the evolutionary loss of three helices in bilaterian ND2 proteins compared to their ancestral homologues. We experimentally validate our model and demonstrate that blocking this interaction with an ND2 fragment identified in our experimental studies prevents Src-mediated upregulation of NMDAR currents in neurons. Our findings establish the mode of interaction between an NMDAR accessory protein with one of the core subunits of the receptor.

Structural Basis of Functional Transitions in Mammalian NMDA Receptors

“…Capturing such a conformation by cryo-EM might require a stabilizer of the ''open'' channel state equivalent to Star-gazin in AMPA receptors. Thus far, several auxiliary subunit proteins for NMDARs have been reported (Ng et al, 2009;Scanlon et al, 2017), however, none of them has been shown to alter ion channel gating. Nevertheless, the activation scheme of NMDARs has similar features to that for GluA2 AMPA receptors in that it is dominated by the movement of the LBD-M3 0 linkers of the GluN2B subunits, which are equivalent to the B/D subunits in GluA2 AMPA receptors.…”

Role of adult hippocampal neurogenesis in the antidepressant actions of lactate

“…These data indicate that conversion of lactate to pyruvate with the concomitant production of NADH potentiates NMDAR activity. Upregulation of NMDAR activity by NADH may occur via NADH dehydrogenase subunit 2 that enables Src kinase regulation of NMDA receptors [ 51 ]. Interestingly, NMDA receptor activation regulates adult hippocampal neurogenesis.…”

Src family kinases, adaptor proteins and the actin cytoskeleton in epithelial-to-mesenchymal transition

“…1 , bottom panel) [ 29 ]. In addition, Salter and colleagues have also demonstrated that NADH dehydrogenase subunit 2 (ND2) anchors SRC kinase to N-methyl D-aspartate receptors (NMDARs) at post-synaptic densities (PSDs) in the hippocampus via an interaction involving SRC UD residues 40–49 and ND2 residues 239–321 [ 30 , 31 ].…”