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.
Highlights
Voltage-gated K+ channels function in macromolecular complexes with accessory subunits to regulate brain function
We report a prolyl cis-trans isomerase NIMAinteracting 1 (Pin1)-dependent mechanism that regulates the composition of the Kv4.2-dipeptidyl peptidase 6 (DPP6) complex, neuronal excitability and cognitive flexibility
The majority of the binding partners are protein synthesis and degradation machinery proteins (Supplementary Fig. 1c, d). This binding was confirmed by the coimmunoprecipitation of endogenous Pin[1] with Kv4.2 in mouse brain lysates (Fig. 1a, uncropped images of all western blots are provided in the Supplementary Information file), and immunostaining of cultured hippocampal neurons revealed that Pin[1] colocalized with Kv4.2 (Fig. 1b)
Summary
Voltage-gated K+ channels function in macromolecular complexes with accessory subunits to regulate brain function. In CA1 hippocampal pyramidal neurons, Kv4.2-mediated currents increase in density from the soma to distal dendrites[1] This gradient is abolished in DPP6 KO mice[17]. We report a Pin1-dependent mechanism that regulates the composition of the Kv4.2-DPP6 complex, neuronal excitability and cognitive flexibility. Using biochemical and electrophysiological techniques, we showed that Pin[1] activity is required for the dissociation of the Kv4.2-DPP6 complex and this action alters neuronal excitability. To confirm these observations, we generated a mouse line containing a Kv4.2 T607A (Kv4.2TA)
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