Phosphorylation of neuroligin-2 by PKA regulates its cell surface abundance and synaptic stabilization

Sci Signal. 2022 Jun 21;15(739):eabg2505. doi: 10.1126/scisignal.abg2505. Epub 2022 Jun 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion Molecules, Neuronal* / genetics
  • Cell Adhesion Molecules, Neuronal* / metabolism
  • Nerve Tissue Proteins* / genetics
  • Nerve Tissue Proteins* / metabolism
  • Phosphorylation
  • Receptors, GABA-A / metabolism
  • Synapses / metabolism
  • Synaptic Transmission / physiology
  • gamma-Aminobutyric Acid / metabolism


  • Cell Adhesion Molecules, Neuronal
  • Nerve Tissue Proteins
  • Receptors, GABA-A
  • neuroligin 2
  • gamma-Aminobutyric Acid