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 R. Durell, Heather A. Cameron, Dax A. Hoffman
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 pThr 607 -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.