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Phosphodiesterase 1C integrates store-operated calcium entry and cAMP signaling in leading-edge protrusions of migrating human arterial myocytes.
Brzezinska, Paulina; Simpson, Nicholas J; Hubert, Fabien; Jacobs, Ariana N; Umana, M Bibiana; MacKeil, Jodi L; Burke-Kleinman, Jonah; Payne, Darrin M; Ferguson, Alastair V; Maurice, Donald H.
Afiliación
  • Brzezinska P; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
  • Simpson NJ; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
  • Hubert F; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
  • Jacobs AN; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
  • Umana MB; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
  • MacKeil JL; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
  • Burke-Kleinman J; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
  • Payne DM; Department of Surgery, Queen's University, Kingston, Ontario, Canada.
  • Ferguson AV; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
  • Maurice DH; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. Electronic address: mauriced@queensu.ca.
J Biol Chem ; 296: 100606, 2021.
Article en En | MEDLINE | ID: mdl-33789162
In addition to maintaining cellular ER Ca2+ stores, store-operated Ca2+ entry (SOCE) regulates several Ca2+-sensitive cellular enzymes, including certain adenylyl cyclases (ADCYs), enzymes that synthesize the secondary messenger cyclic AMP (cAMP). Ca2+, acting with calmodulin, can also increase the activity of PDE1-family phosphodiesterases (PDEs), which cleave the phosphodiester bond of cAMP. Surprisingly, SOCE-regulated cAMP signaling has not been studied in cells expressing both Ca2+-sensitive enzymes. Here, we report that depletion of ER Ca2+ activates PDE1C in human arterial smooth muscle cells (HASMCs). Inhibiting the activation of PDE1C reduced the magnitude of both SOCE and subsequent Ca2+/calmodulin-mediated activation of ADCY8 in these cells. Because inhibiting or silencing Ca2+-insensitive PDEs had no such effects, these data identify PDE1C-mediated hydrolysis of cAMP as a novel and important link between SOCE and its activation of ADCY8. Functionally, we showed that PDE1C regulated the formation of leading-edge protrusions in HASMCs, a critical early event in cell migration. Indeed, we found that PDE1C populated the tips of newly forming leading-edge protrusions in polarized HASMCs, and co-localized with ADCY8, the Ca2+ release activated Ca2+ channel subunit, Orai1, the cAMP-effector, protein kinase A, and an A-kinase anchoring protein, AKAP79. Because this polarization could allow PDE1C to control cAMP signaling in a hyper-localized manner, we suggest that PDE1C-selective therapeutic agents could offer increased spatial specificity in HASMCs over agents that regulate cAMP globally in cells. Similarly, such agents could also prove useful in regulating crosstalk between Ca2+/cAMP signaling in other cells in which dysregulated migration contributes to human pathology, including certain cancers.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arterias / Transducción de Señal / Calcio / AMP Cíclico / Células Musculares / Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Biol Chem Año: 2021 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arterias / Transducción de Señal / Calcio / AMP Cíclico / Células Musculares / Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Biol Chem Año: 2021 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos