The signaling proteins GPR158 and RGS7 modulate excitability of L2/3 pyramidal neurons and control A-type potassium channel in the prelimbic cortex

J Biol Chem. 2019 Aug 30;294(35):13145-13157. doi: 10.1074/jbc.RA119.007533. Epub 2019 Jul 16.


Stress profoundly affects physiological properties of neurons across brain circuits and thereby increases the risk for depression. However, the molecular and cellular mechanisms mediating these effects are poorly understood. In this study, we report that chronic physical restraint stress in mice decreases excitability specifically in layer 2/3 of pyramidal neurons within the prelimbic subarea of the prefrontal cortex (PFC) accompanied by the induction of depressive-like behavioral states. We found that a complex between G protein-coupled receptor (GPCR) 158 (GPR158) and regulator of G protein signaling 7 (RGS7), a regulatory GPCR signaling node recently discovered to be a key modulator of affective behaviors, plays a key role in controlling stress-induced changes in excitability in this neuronal population. Deletion of GPR158 or RGS7 enhanced excitability of layer 2/3 PFC neurons and prevented the impact of stress. Investigation of the underlying molecular mechanisms revealed that the A-type potassium channel Kv4.2 subunit is a molecular target of the GPR158-RGS7 complex. We further report that GPR158 physically associates with Kv4.2 channel and promotes its function by suppressing inhibitory modulation by cAMP-protein kinase A (PKA)-mediated phosphorylation. Taken together, our observations reveal a critical mechanism that adjusts neuronal excitability in L2/3 pyramidal neurons of the PFC and may thereby modulate the effects of stress on depression.

Keywords: G protein-coupled receptor (GPCR); KV4.2 channels; depression; heterotrimeric G protein; intrinsic excitability; ion channel; neuromodulation; orphan receptors; regulator of G protein signaling (RGS); regulator of G protein signaling 7 (RGS7); stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Potassium Channels, Voltage-Gated / metabolism*
  • Prefrontal Cortex / metabolism*
  • Pyramidal Cells / metabolism*
  • RGS Proteins / deficiency
  • RGS Proteins / metabolism*
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction*


  • GPR158 protein, mouse
  • Potassium Channels, Voltage-Gated
  • RGS Proteins
  • Receptors, G-Protein-Coupled
  • Rgs7 protein, mouse