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

Brain Res. 2007 Aug 8;1162:19-31. doi: 10.1016/j.brainres.2007.05.051. Epub 2007 Jun 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Biotinylation / methods
  • Cells, Cultured
  • Cerebellum / metabolism*
  • Chlorocebus aethiops
  • Gene Expression Regulation, Developmental / physiology*
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Humans
  • Interleukin-16 / genetics
  • Interleukin-16 / metabolism*
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Membrane Potentials / radiation effects
  • Mice
  • Mice, Inbred C57BL
  • Mutagenesis / physiology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / drug effects
  • Neurons / physiology*
  • Neurons / radiation effects
  • Patch-Clamp Techniques / methods
  • RNA, Small Interfering / pharmacology
  • Shal Potassium Channels / physiology*
  • Transfection / methods

Substances

  • Interleukin-16
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Shal Potassium Channels
  • neuronal interleukin-16
  • Green Fluorescent Proteins