Molecular motor KIF5A is essential for GABA(A) receptor transport, and KIF5A deletion causes epilepsy

Neuron. 2012 Dec 6;76(5):945-61. doi: 10.1016/j.neuron.2012.10.012.

Abstract

KIF5 (also known as kinesin-1) family members, consisting of KIF5A, KIF5B, and KIF5C, are microtubule-dependent molecular motors that are important for neuronal function. Among the KIF5s, KIF5A is neuron specific and highly expressed in the central nervous system. However, the specific roles of KIF5A remain unknown. Here, we established conditional Kif5a-knockout mice in which KIF5A protein expression was postnatally suppressed in neurons. Epileptic phenotypes were observed by electroencephalogram abnormalities in knockout mice because of impaired GABA(A) receptor (GABA(A)R)-mediated synaptic transmission. We also identified reduced cell surface expression of GABA(A)R in knockout neurons. Importantly, we identified that KIF5A specifically interacted with GABA(A)R-associated protein (GABARAP) that is known to be involved in GABA(A)R trafficking. KIF5A regulated neuronal surface expression of GABA(A)Rs via an interaction with GABARAP. These results provide an insight into the molecular mechanisms of KIF5A, which regulate inhibitory neural transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Biophysics
  • Brain Waves / genetics
  • CA1 Region, Hippocampal / pathology
  • Cytoskeletal Proteins / metabolism
  • Disease Models, Animal
  • Electric Stimulation
  • Electroencephalography
  • Endocytosis / drug effects
  • Endocytosis / genetics
  • Epilepsy / genetics*
  • Female
  • GABA Plasma Membrane Transport Proteins / genetics
  • GABA Plasma Membrane Transport Proteins / metabolism
  • Glycosylation / drug effects
  • Golgi Apparatus / drug effects
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism
  • Green Fluorescent Proteins / genetics
  • Humans
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / genetics
  • Kinesin / deficiency*
  • Kinesin / genetics
  • Locomotion / genetics
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Neurons / physiology
  • Neurons / ultrastructure
  • Patch-Clamp Techniques
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Protein Transport / genetics
  • Receptors, GABA-A / metabolism*
  • Synapsins / genetics
  • Transfection

Substances

  • Cytoskeletal Proteins
  • GABA Plasma Membrane Transport Proteins
  • GABARAP protein, mouse
  • KIF5A protein, human
  • Membrane Proteins
  • MicroRNAs
  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Protein Subunits
  • Receptors, GABA-A
  • Synapsins
  • Green Fluorescent Proteins
  • Kinesin