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

Jia–Hua Hu, Cole Malloy, G. Travis Tabor, Jakob J. Gutzmann, Ying Liu, Daniel Abebe, Rose-Marie Karlsson, Stewart Durell, Heather A. Cameron and Dax A. Hoffman ()
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Jia–Hua Hu: The Eunice Kennedy Shriver National Institute of Child Health and Human Development
Cole Malloy: The Eunice Kennedy Shriver National Institute of Child Health and Human Development
G. Travis Tabor: The Eunice Kennedy Shriver National Institute of Child Health and Human Development
Jakob J. Gutzmann: The Eunice Kennedy Shriver National Institute of Child Health and Human Development
Ying Liu: The Eunice Kennedy Shriver National Institute of Child Health and Human Development
Daniel Abebe: The Eunice Kennedy Shriver National Institute of Child Health and Human Development
Rose-Marie Karlsson: National Institute of Mental Health
Stewart Durell: National Cancer Institute
Heather A. Cameron: National Institute of Mental Health
Dax A. Hoffman: The Eunice Kennedy Shriver National Institute of Child Health and Human Development

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15390-x

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