Modulation of Kv4.2 K+ currents by neuronal interleukin-16, a PDZ domain-containing protein expressed in the hippocampus and cerebellum

doi:10.1016/j.brainres.2007.05.051

Brain Research

Volume 1162, 8 August 2007, Pages 19-31

https://doi.org/10.1016/j.brainres.2007.05.051 Get rights and content

Abstract

Neuronal interleukin-16 (NIL-16) is a multi-PDZ domain protein expressed in post-mitotic neurons of the hippocampus and cerebellum. NIL-16 contains four PDZ domains, two of which are located within the neuron-specific N-terminal region. In yeast two-hybrid systems, the N-terminus of NIL-16 interacts with several ion channel proteins, including the Kv4.2 subunit of A-type K⁺ channels. Here we provide evidence that NIL-16, through interactions with Kv4.2, influences Kv4.2 channel function and subcellular distribution. Specifically, coexpression of NIL-16 with Kv4.2 in COS-7 cells results in a significant reduction in whole-cell A-type current densities; however, when the Kv4.2 PDZ-ligand domain is mutated, Kv4.2 current densities are not affected by NIL-16 coexpression. Moreover, single-channel conductance was not influenced by the presence of NIL-16. In hippocampal neurons, A-type current densities are increased by conditions that inhibit interactions between NIL-16 and Kv4.2, such as overexpression of the Kv4.2 C-terminal PDZ-ligand domain and treatment with small-interfering RNA duplexes that reduce NIL-16 expression. Results of surface biotinylation assays using COS-7 cells suggest that Kv4.2 surface expression levels are reduced by coexpression with NIL-16. In addition, coexpression of NIL-16 with Kv4.2 induces Kv4.2 to form dense intracellular clusters; whereas without NIL-16, Kv4.2 channels cells are dispersed. Taken together, these data suggest that interactions between Kv4.2 and NIL-16 may reduce the number of functional Kv4.2-containing channels on the cell surface. In summary, NIL-16 may provide a novel form of A-type K⁺ channel modulation that is localized specifically to neurons of the hippocampus and cerebellum.

Introduction

Transient A-type K⁺ currents modulate neuronal excitability and synaptic plasticity in the hippocampus. For example, down-regulation of A-type K⁺ currents in hippocampal neurons increases the amplitude of back-propagating dendritic action potentials (Hoffman et al., 1997, Johnston et al., 1999) and enhances membrane excitability (Castro et al., 2001, Hu and Gereau, 2003, Varga et al., 2004). Kv4.2 is the predominant pore-forming subunit of A-type K⁺ channels in hippocampal pyramidal neurons (Jin et al., 2003, Kim et al., 2005) and localizes to somatodendritic regions where it forms clusters at postsynaptic sites (Jinno et al., 2005, Burkhalter et al., 2006). Postsynaptic Kv4.2-containing channels may affect NMDA-receptor-dependent plasticity by influencing membrane potentials sensed by NMDA-receptors (Alonso and Widmer, 1997, Schrader et al., 2002, Watanabe et al., 2002). Consistent with an important role in modulating hippocampal synaptic plasticity, Kv4.2 gene deletion in mice largely eliminates dendritic A-type currents and reduces the threshold for induction of long-term potentiation in hippocampal CA1 pyramidal neurons (Chen et al., 2006).

Activation of PKC, PKA and/or certain neurotransmitter receptors have been shown to influence the biophysical properties of Kv4.2-mediated K⁺ currents (Hoffman and Johnston, 1998, Hoffman and Johnston, 1999). These effects are believed to be secondary to the activation of the mitogen-activated protein kinase ERK (Hu and Gereau, 2003, Watanabe et al., 2002, Yuan et al., 2002), which directly phosphorylates Kv4.2 (Adams et al., 2000, Schrader et al., 2006). In addition to phosphorylation-dependent mechanisms, proteins that specifically interact with Kv4.2 subunits can influence channel function. For example, KChiPs, which co-assemble with Kv4 family subunits, modulate the surface expression and biophysical properties of Kv4-containing channels (Rhodes et al., 2004, Schrader et al., 2006, Shibata et al., 2003). The synapse associated multi-PDZ (PSD-95/Disc-large/ZO-1 homology) domain protein, PSD-95, interacts with the C-terminal PDZ binding domain of Kv4.2 and increases Kv4.2 surface expression, cluster formation, and whole-cell current densities in heterologous expression systems (Wong et al., 2002). Neuronal interleukin-16 (NIL-16) is a multi-PDZ domain protein that has also been shown to interact with Kv4.2 (Kurschner and Yuzaki, 1999). Here we investigate the effects of the interaction between NIL-16 and Kv4.2.

NIL-16 is a cytosolic protein that is expressed exclusively in post-mitotic neurons of the hippocampus and cerebellum (Kurschner and Yuzaki, 1999). The N-terminal region (corresponding to amino acids 1–698) of NIL-16 is expressed only in neurons. The remaining C-terminal region of NIL-16 is identical to pro-IL-16, the precursor of IL-16, a cytokine with functions believed previously to be restricted to the immune system. Similar to pro-IL-16, NIL-16 can be cleaved by caspase-3 to result in the secretion of IL-16 (Kurschner and Yuzaki, 1999); thus, NIL-16 is a neuron-specific precursor of IL-16 that may serve as a neuronal signaling molecule. In addition to the role of NIL-16 as a precursor of IL-16, NIL-16 contains four PDZ domains, two of which are within the neuron-specific N-terminal region. Using a yeast two-hybrid screen, Kurschner and Yuzaki (1999) identified several neuronal ion channels (each of which contained the C-terminal PDZ-interacting consensus sequence x-S-x-V/I/L) as potential ligands for the N-terminal region of NIL-16. Ion channels identified in this screen include NMDA receptor subunits (NR2A-D), inward rectifier K⁺ channels (Kir2.1, 2.3 and Kir4.1, 4.2), the Ca²⁺ channel α1C subunit, and A-type K⁺ channel subunits (Kv4.1–3). Considering (1) that NIL-16 is found only in hippocampal and cerebellar neurons, (2) the role of Kv4.2 channels in influencing neuronal excitability, and (3) the identification of NIL-16 as a Kv4.2 binding protein, it is possible that NIL-16, through functional interactions with the Kv4.2 subunit, influences neuronal excitability in the hippocampus and cerebellum.

In this study, we investigate the ability of NIL-16 and Kv4.2 to interact in vivo and the influence of NIL-16 on the function of Kv4.2-containing channels. We show that coexpression of NIL-16 with Kv4.2 in heterologous expression systems reduces whole-cell A-type current densities but does not influence single-channel conductance, results in intracellular clustering of Kv4.2, and decreases Kv4.2 surface expression levels. Results of coimmunoprecipitation assays suggest that NIL-16 and Kv4.2 are present in the same protein complexes in the hippocampus and cerebellum. In addition, in primary cultures of hippocampal neurons, A-type current densities are increased by conditions which either disrupt binding between Kv4.2 and NIL-16 or reduce NIL-16 expression levels. In conclusion, interactions between NIL-16 and Kv4.2-containing channels may provide a novel form of A-type K⁺ current modulation that specifically occurs in neurons of the hippocampus and cerebellum.

Section snippets

NIL-16 reduces Kv4.2 current density in COS-7 cells

To test the hypothesis that NIL-16 influences Kv4.2-mediated currents, we first compared Kv4.2 currents in COS-7 cells coexpressing Kv4.2 with either NIL-16/GFP or a control GFP vector. Kv4.2-dependent current densities of cells cotransfected with the control vector were significantly greater than of cells cotransfected with NIL-16/GFP at clamp potentials of − 40 to + 30 mV (Figs. 1A and B). Time courses of inactivation were similar regardless of NIL-16 transfection.

It is possible that the

Discussion

In the present study, we provide the following evidence that NIL-16 interacts (either directly or indirectly) with Kv4.2 and reduces Kv4.2 subunit-containing channel current densities: In heterologous cells, NIL-16 coexpression reduces whole-cell Kv4.2-current densities; however, NIL-16 coexpression does not affect Kv4.2-current densities when the PDZ-ligand domain of Kv4.2 is mutated (Fig. 1); NIL-16 and Kv4.2 can be coimmunoprecipitated from mixed hippocampal and cerebellar lysates (Fig. 3);

Expression constructs and site-directed mutagenesis

Full-length cDNA encoding Kv4.2 was amplified by RT–PCR and inserted into the mammalian expression vector pcDNA3 (Invitrogen). To introduce point mutations to the C-terminus of Kv4.2 (Kv4.2mutC), two amino acids within the C-terminal amino acid sequence of Kv4.2 (Ser-Ala-Leu-COOH) were mutated to produce the end sequence Gly-Ala-Gly-COOH with PCR using a 3′oligonucleotide primer and that encoded the mutated sequence. Using the yeast two-hybrid system as a read-out, protein interaction between

Acknowledgments

We thank Dr. M. Yuzaki for guidance and helpful discussion. We thank Lorna Johnston and S. Northcutt for technical assistance.

The actin monoclonal antibody developed by Jim Jung-Ching Lin was obtained from the Developmental Studies Hybridoma Band developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, IA 52242.

The project was supported by an NIH F33 grant awarded to J. Blundon (Grant Number F33NS011104-01), by a Rhodes

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Research ReportModulation of Kv4.2 K+ currents by neuronal interleukin-16, a PDZ domain-containing protein expressed in the hippocampus and cerebellum

Abstract

Introduction

Section snippets

NIL-16 reduces Kv4.2 current density in COS-7 cells

Discussion

Expression constructs and site-directed mutagenesis

Acknowledgments

J. Biol. Chem.

J. Biol. Chem.

Neuron

Neuroscience

Curr. Opin. Neurobiol.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK

J. Neurochem.

Clustering of KV4.2 potassium channels in postsynaptic membrane of rat supraoptic neurons: an ultrastructural study

Neuroscience

Structure and function of Kv4-family transient potassium channels

Physiol. Rev.

Differential expression of I(A) channel subunits Kv4.2 and Kv4.3 in mouse visual cortical neurons and synapses

J. Neurosci.

Hippocampal heterotopia lack functional Kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy

J. Neurosci.

Effects of metal-binding properties of human Kv channel-interacting proteins on their molecular structure and binding with Kv4.2 channel

Protein J.

Voltage clamp studies of a transient outward membrane current in gastropod neural somata

J. Physiol.

Research Report
Modulation of Kv4.2 K⁺ currents by neuronal interleukin-16, a PDZ domain-containing protein expressed in the hippocampus and cerebellum