Suppressive effects of 4-phenylbutyrate on the aggregation of Pael receptors and endoplasmic reticulum stress

J Neurochem. 2006 Jun;97(5):1259-68. doi: 10.1111/j.1471-4159.2006.03782.x. Epub 2006 Mar 15.


Endoplasmic reticulum (ER) stress is defined as an accumulation of unfolded proteins in the endoplasmic reticulum. 4-phenylbutyrate (4-PBA) has been demonstrated to promote the normal trafficking of the DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) mutant from the ER to the plasma membrane and to restore activity. We have reported that 4-PBA protected against cerebral ischemic injury and ER stress-induced neuronal cell death. In this study, we revealed that 4-PBA possesses chemical chaperone activity in vitro, which prevents the aggregation of denatured alpha-lactalbumin and bovine serum albumin (BSA). Furthermore, we investigated the effects of 4-PBA on the accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R) pathologically relevant to the loss of dopaminergic neurons in autosomal recessive juvenile parkinsonism (AR-JP). Interestingly, 4-PBA restored the normal expression of Pael-R protein and suppressed ER stress induced by the overexpression of Pael-R. In addition, we showed that 4-PBA attenuated the activation of ER stress-induced signal transduction pathways and subsequent neuronal cell death. Moreover, 4-PBA restored the viability of yeasts that fail to induce an ER stress response under ER stress conditions. These results suggest that 4-PBA suppresses ER stress by directly reducing the amount of misfolded protein, including Pael-R accumulated in the ER.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Line, Tumor
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Inclusion Bodies / drug effects
  • Inclusion Bodies / metabolism
  • Lactalbumin / drug effects
  • Lactalbumin / metabolism
  • Molecular Chaperones / metabolism
  • Molecular Chaperones / pharmacology
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / physiopathology
  • Phenylbutyrates / metabolism
  • Phenylbutyrates / pharmacology*
  • Protein Folding
  • Receptor Aggregation / drug effects*
  • Receptors, G-Protein-Coupled / drug effects
  • Receptors, G-Protein-Coupled / metabolism*
  • Saccharomyces cerevisiae
  • Serum Albumin, Bovine / drug effects
  • Serum Albumin, Bovine / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stress, Physiological / metabolism*
  • Tunicamycin / pharmacology


  • Antineoplastic Agents
  • GPR37 receptor, human
  • Molecular Chaperones
  • Neuroprotective Agents
  • Phenylbutyrates
  • Receptors, G-Protein-Coupled
  • Tunicamycin
  • Serum Albumin, Bovine
  • 4-phenylbutyric acid
  • Lactalbumin