Store-operated calcium entry promotes the degradation of the transcription factor Sp4 in resting neurons

Sci Signal. 2014 Jun 3;7(328):ra51. doi: 10.1126/scisignal.2005242.


Calcium (Ca(2+)) signaling activated in response to membrane depolarization regulates neuronal maturation, connectivity, and plasticity. Store-operated Ca(2+) entry (SOCE) occurs in response to depletion of Ca(2+) from endoplasmic reticulum (ER), mediates refilling of this Ca(2+) store, and supports Ca(2+) signaling in nonexcitable cells. We report that maximal activation of SOCE occurred in cerebellar granule neurons cultured under resting conditions and that this Ca(2+) influx promoted the degradation of transcription factor Sp4, a regulator of neuronal morphogenesis and function. Lowering the concentration of extracellular potassium, a condition that reduces neuronal excitability, stimulated depletion of intracellular Ca(2+) stores, resulted in the relocalization of the ER Ca(2+) sensor STIM1 into punctate clusters consistent with multimerization and accumulation at junctions between the ER and plasma membrane, and induced a Ca(2+) influx with characteristics of SOCE. Compounds that block SOCE prevented the ubiquitylation and degradation of Sp4 in neurons exposed to a low concentration of extracellular potassium. Knockdown of STIM1 blocked degradation of Sp4, whereas expression of constitutively active STIM1 decreased Sp4 abundance under depolarizing conditions. Our findings indicated that, in neurons, SOCE is induced by hyperpolarization, and suggested that this Ca(2+) influx pathway is a distinct mechanism for regulating neuronal gene expression.

Publication types

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

MeSH terms

  • Animals
  • Bacterial Proteins / metabolism
  • Blotting, Western
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology*
  • Cells, Cultured
  • Cerebellum / cytology
  • DNA Primers / genetics
  • Fluorescent Antibody Technique
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Imidazoles / pharmacology
  • Immunohistochemistry
  • Immunoprecipitation
  • Luminescent Proteins / metabolism
  • Membrane Glycoproteins / metabolism*
  • Neurons / metabolism*
  • Plasmids / genetics
  • Potassium / metabolism
  • Proteolysis / drug effects*
  • Rats
  • Rats, Long-Evans
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sp4 Transcription Factor / metabolism*
  • Stromal Interaction Molecule 1
  • Ubiquitination


  • Bacterial Proteins
  • Calcium Channel Blockers
  • DNA Primers
  • Imidazoles
  • Luminescent Proteins
  • Membrane Glycoproteins
  • Sp4 Transcription Factor
  • Sp4 protein, rat
  • Stim1 protein, rat
  • Stromal Interaction Molecule 1
  • yellow fluorescent protein, Bacteria
  • 1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
  • Potassium
  • Calcium