The Intellectual Disability Protein RAB39B Selectively Regulates GluA2 Trafficking to Determine Synaptic AMPAR Composition

Nat Commun. 2015 Mar 18;6:6504. doi: 10.1038/ncomms7504.

Abstract

RAB39B is a member of the RAB family of small GTPases that controls intracellular vesicular trafficking in a compartment-specific manner. Mutations in the RAB39B gene cause intellectual disability comorbid with autism spectrum disorder and epilepsy, but the impact of RAB39B loss of function on synaptic activity is largely unexplained. Here we show that protein interacting with C-kinase 1 (PICK1) is a downstream effector of GTP-bound RAB39B and that RAB39B-PICK1 controls trafficking from the endoplasmic reticulum to the Golgi and, hence, surface expression of GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). The role of AMPARs in synaptic transmission varies depending on the combination of subunits (GluA1, GluA2 and GluA3) they incorporate. RAB39B downregulation in mouse hippocampal neurons skews AMPAR composition towards non GluA2-containing Ca(2+)-permeable forms and thereby alters synaptic activity, specifically in hippocampal neurons. We posit that the resulting alteration in synaptic function underlies cognitive dysfunction in RAB39B-related disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Carrier Proteins / metabolism
  • Chlorocebus aethiops
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism
  • Electrophysiology
  • Gene Expression Regulation
  • Glutathione Transferase / metabolism
  • Glycosylation
  • Golgi Apparatus / metabolism
  • Green Fluorescent Proteins / metabolism
  • Guanosine Triphosphate / chemistry
  • HEK293 Cells
  • Hippocampus / metabolism
  • Humans
  • Intellectual Disability / genetics*
  • Mice
  • Mutation
  • Neurons / metabolism
  • Nuclear Proteins / metabolism
  • Protein Structure, Tertiary
  • Protein Transport
  • Receptors, AMPA / metabolism*
  • Synapses / metabolism*
  • Synaptic Transmission
  • Two-Hybrid System Techniques
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Carrier Proteins
  • Nuclear Proteins
  • PICk1 protein, human
  • Receptors, AMPA
  • Green Fluorescent Proteins
  • Guanosine Triphosphate
  • Glutathione Transferase
  • RAB39B protein, mouse
  • Rab39B protein, human
  • rab GTP-Binding Proteins
  • glutamate receptor ionotropic, AMPA 2