Activity-dependent isomerization of Kv4.2 by Pin1 regulates cognitive flexibility

Nat Commun. 2020 Mar 26;11(1):1567. doi: 10.1038/s41467-020-15390-x.


Voltage-gated K+ channels function in macromolecular complexes with accessory subunits to regulate brain function. Here, we describe a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1)-dependent mechanism that regulates the association of the A-type K+ channel subunit Kv4.2 with its auxiliary subunit dipeptidyl peptidase 6 (DPP6), and thereby modulates neuronal excitability and cognitive flexibility. We show that activity-induced Kv4.2 phosphorylation triggers Pin1 binding to, and isomerization of, Kv4.2 at the pThr607-Pro motif, leading to the dissociation of the Kv4.2-DPP6 complex. We generated a novel mouse line harboring a knock-in Thr607 to Ala (Kv4.2TA) mutation that abolished dynamic Pin1 binding to Kv4.2. CA1 pyramidal neurons of the hippocampus from these mice exhibited altered Kv4.2-DPP6 interaction, increased A-type K+ current, and reduced neuronal excitability. Behaviorally, Kv4.2TA mice displayed normal initial learning but improved reversal learning in both Morris water maze and lever press paradigms. These findings reveal a Pin1-mediated mechanism regulating reversal learning and provide potential targets for the treatment of neuropsychiatric disorders characterized by cognitive inflexibility.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cognition*
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
  • HEK293 Cells
  • Humans
  • Imidazoles / pharmacology
  • Ion Channel Gating / drug effects
  • Isomerism
  • Learning
  • Mice
  • Models, Biological
  • NIMA-Interacting Peptidylprolyl Isomerase / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphorylation / drug effects
  • Phosphothreonine / metabolism
  • Protein Binding
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism
  • Pyridines / pharmacology
  • Seizures / metabolism
  • Seizures / pathology
  • Shal Potassium Channels / chemistry
  • Shal Potassium Channels / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Imidazoles
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Pyridines
  • Shal Potassium Channels
  • Phosphothreonine
  • p38 Mitogen-Activated Protein Kinases
  • DPP6 protein, mouse
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • Pin1 protein, mouse
  • SB 203580