Research ArticleNeuroscience

Store-Operated Calcium Entry Promotes the Degradation of the Transcription Factor Sp4 in Resting Neurons

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Sci. Signal.  03 Jun 2014:
Vol. 7, Issue 328, pp. ra51
DOI: 10.1126/scisignal.2005242

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Calcium (Ca2+) signaling activated in response to membrane depolarization regulates neuronal maturation, connectivity, and plasticity. Store-operated Ca2+ entry (SOCE) occurs in response to depletion of Ca2+ from endoplasmic reticulum (ER), mediates refilling of this Ca2+ store, and supports Ca2+ signaling in nonexcitable cells. We report that maximal activation of SOCE occurred in cerebellar granule neurons cultured under resting conditions and that this Ca2+ 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 Ca2+ stores, resulted in the relocalization of the ER Ca2+ sensor STIM1 into punctate clusters consistent with multimerization and accumulation at junctions between the ER and plasma membrane, and induced a Ca2+ 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 Ca2+ influx pathway is a distinct mechanism for regulating neuronal gene expression.

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