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

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 NIMAinteracting 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 Pin1mediated mechanism regulating reversal learning and provide potential targets for the treatment of neuropsychiatric disorders characterized by cognitive inflexibility.

R-type voltage-gated Ca2+channels mediate A-type K+current regulation of synaptic input in hippocampal dendrites

“…Furthermore, Kv4.2 surface expression is bidirectionally regulated by local signaling of the Ca 2+activated phosphatase calcineurin (CaN) and PKA through the postsynaptic scaffolding protein AKAP79/150 (63). We recently reported a role for a proline isomerase, Pin1 in activity-dependent downregulation of Kv4.2 function downstream of p38 phosphorylation of T607 (58). Thus, differential localization of kinases and phosphatases along the proximal-distal axis of CA1 pyramidal neurons could underlie the IA gradient and is an important topic for further study.…”

“…Unlike the DIV6-8 neurons used above, these neurons are greater in size and express a more substantial proportion of contaminating delayed rectifier K + currents. Therefore, IA was isolated as previously described using large voltage steps and subtraction of the sustained outward current (Isus) from the total outward current (Itot) ( Figure 6A) (58). IA was selectively reduced in whole-cell recordings from Cav2.3 KOs when compared to WT mouse neurons while Isus was unchanged ( Figure 6B).…”

P38 Regulates Kainic Acid-Induced Seizure and Neuronal Firing via Kv4.2 Phosphorylation

“…In pyramidal neurons, this downregulation facilitates an increase in somatodendritic excitability, enhancing susceptibility to network hyperexcitability in the hippocampus [ 39 , 40 , 41 ]. We have recently identified a specific MAPK, p38α, as a potent regulator of the Kv4.2 complex [ 42 ]. The p38 phosphorylation of Kv4.2 C-terminal motifs triggers a molecular cascade that facilitates the dissociation of Kv4.2 from its auxiliary subunit DPP6 [ 42 ].…”

“…We have recently identified a specific MAPK, p38α, as a potent regulator of the Kv4.2 complex [ 42 ]. The p38 phosphorylation of Kv4.2 C-terminal motifs triggers a molecular cascade that facilitates the dissociation of Kv4.2 from its auxiliary subunit DPP6 [ 42 ]. This cascade is particularly intriguing in the context of TLE, as it occurs in an activity-dependent fashion, representing a novel mechanism that may be integral in regulating seizure susceptibility [ 42 ].…”

CP Poly(A) RNA Binding Immunity via Outside-in Glycosyltransfer with MT of BTRC-Activating L12535 and PIN1 Subnetworks for Cognition in PFC|CD14

“…RAS inhibition attenuates cognitive impairment via reducing blood-brain barrier permeability in hypertensive subjects [4]. Activity-dependent isomerization of Kv4.2 by Pin1 regulates cognitive exibility [5]. PIN-1 promoter polymorphisms in mild cognitive impairment and susceptibility to Alzheimer's disease as a preliminary report [6].…”