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- Title
Phosphorylation of neuroligin-2 by PKA regulates its cell surface abundance and synaptic stabilization.
- Authors
Halff, Els F.; Hannan, Saad; Kwanthongdee, Jaturon; Lesept, Flavie; Smart, Trevor G.; Kittler, Josef T.
- Abstract
The trans-synaptic adhesion molecule neuroligin-2 (NL2) is essential for the development and function of inhibitory synapses. NL2 recruits the postsynaptic scaffold protein gephyrin, which, in turn, stabilizes γ-aminobutyric acid type A receptors (GABAARs) in the postsynaptic domain. Thus, the amount of NL2 at the synapse can control synaptic GABAAR concentration to tune inhibitory neurotransmission efficacy. Here, using biochemistry, imaging, single-particle tracking, and electrophysiology, we uncovered a key role for cAMP-dependent protein kinase (PKA) in the synaptic stabilization of NL2. We found that PKA-mediated phosphorylation of NL2 at Ser714 caused its dispersal from the synapse and reduced NL2 surface amounts, leading to a loss of synaptic GABAARs. Conversely, enhancing the stability of NL2 at synapses by abolishing PKA-mediated phosphorylation led to increased inhibitory signaling. Thus, PKA plays a key role in regulating NL2 function and GABA-mediated synaptic inhibition. Adjusting synaptic GABA signaling with PKA: In neurons, the adhesion molecule neuroligin-2 (NL2) recruits a scaffold protein that supports the surface localization of receptors for the inhibitory neurotransmitter GABA. Phosphorylation of NL2 disrupts its interaction with the scaffold protein and decreases GABA type A receptor abundance, thereby decreasing the strength of GABA signaling. Halff et al. found that the phosphorylation of NL2 was mediated by the kinase PKA. In cultured rat neurons, this phosphorylation event induced the dispersal of NL2 from the synaptic surface, which decreased the surface abundance of the GABA receptor and dampened inhibitory currents. In contrast, GABAergic signaling was enhanced in neurons expressing a form of NL2 in which the phosphosite was mutated to alanine. The findings may provide insight for neurological conditions in which altered inhibitory circuit activity is implicated.
- Subjects
CYCLIC-AMP-dependent protein kinase; NEUROTRANSMITTER receptors; SCAFFOLD proteins; AMPA receptors; GABA receptors; NEUROLOGICAL disorders; PHOSPHORYLATION; SYNAPSES
- Publication
Science Signaling, 2022, Vol 15, Issue 739, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abg2505