A critical gating switch at a modulatory site in neuronal Kir3 channels

Scott K. Adney, Junghoon Ha, Xuan Yu Meng, Takeharu Kawano, Diomedes E. Logothetis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Inwardly rectifying potassium channels enforce tight control of resting membrane potential in excitable cells. The Kir3.2 channel, a member of the Kir3 subfamily of G-protein-activated potassium channels (GIRKs), plays several roles in the nervous system, including key responsibility in the GABAB pathway of inhibition, in pain perception pathways via opioid receptors, and is also involved in alcoholism. PKC phosphorylation acts on the channel to reduce activity, yet the mechanism is incompletely understood. Using the heterologous Xenopus oocyte system combined with molecular dynamics simulations, we show that PKC modulation of channel activity is dependent on Ser-196 in Kir3.2 such that, when this site is phosphorylated, the channel is less sensitive to PKC inhibition. This reduced inhibition is dependent on an interaction between phospho-Ser (SEP)-196 and Arg-201, reducing Arg-201 interaction with the sodium-binding site Asp-228. Neutralization of either SEP-196 or Arg-201 leads to a channel with reduced activity and increased sensitivity to PKC inhibition. This study clarifies the role of Ser-196 as an allosteric modulator of PKC inhibition and suggests that the SEP-196/Arg-201 interaction is critical for maintaining maximal channel activity.

Original languageEnglish (US)
Pages (from-to)14397-14405
Number of pages9
JournalJournal of Neuroscience
Issue number42
StatePublished - Oct 21 2015


  • GIRK
  • Kir3
  • PIP
  • PKC

ASJC Scopus subject areas

  • General Neuroscience


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