title: Spongionella Secondary Metabolites Regulate Store Operated Calcium Entry Modulating Mitochondrial Functioning in SH-SY5Y Neuroblastoma Cells.
abstract: OBJECTIVE
  The effect of four secondary metabolites isolated from sponge Spongionella, gracilins H, A, L and tetrahydroaplysulphurin-1 on Calcium ion (Ca2+) fluxes were studied in SH-SY5Y neuroblastoma cells.
  
  
  RESULTS
  These compounds did not modify cytosolic baseline Ca2+-levels. Nevertheless, when cytosolic Ca2+-influx through store operated calcium channels (SOC channels) was stimulated with Thapsigargin (Tg), a strong inhibition was observed in the presence of gracilin A, gracilin L and tetrahydroaplysulphurin-1. Since these compounds were able to protect mitochondria from oxidative stress, the role of this organelle in the Ca2+-influx inhibition was tested. In this sense, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) and Cyclosporine A (CsA) were used. Surprisingly, both the inhibitory effect over Tg-sensitive stores and Ca2+ influx through SOC channels produced by FCCP were abolished with different potencies by Spongionella compounds in a similar way than CsA. CsA is able to avoid Mitochondrial Permeability Transition Pore (mPTP) opening. As well as CsA, Spongionella compounds reverted mPTP opening induced by FCCP. In the case of CsA the mPTP blockade is due to the direct binding to Cyclophilin D (Cyp D), a mitochondrial matrix protein. This association was also observed between gracilin L and tetrahydroaplysulphurin-1 and Cyp D. Therefore, Spongionella compounds modulate mitochondrial activity by preventing mPTP opening by binding to Cyp D.
  
  
  CONCLUSIONS
  These effects make Spongionella compounds as new family of compounds with promising activity in human diseases where mitochondrial alterations are implicated.
authors.affiliation: Departamento de Farmacologx00ED;a, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
authors.forename: Jon Andoni
authors.initials: JA
authors.lastname: Sánchez
authors.forename: Amparo
authors.initials: A
authors.lastname: Alfonso
authors.forename: Marta
authors.initials: M
authors.lastname: Leirós
authors.forename: Eva
authors.initials: E
authors.lastname: Alonso
authors.forename: Mostafa E
authors.initials: ME
authors.lastname: Rateb
authors.forename: Marcel
authors.initials: M
authors.lastname: Jaspars
authors.forename: Wael E
authors.initials: WE
authors.lastname: Houssen
authors.forename: Rainer
authors.initials: R
authors.lastname: Ebel
authors.forename: Luís M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011161:Porifera / Q000737:chemistry*; D064210:Secondary Metabolism; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D004224:Diterpenes; C544220:gracilin L; D019284:Thapsigargin; D016572:Cyclosporine; D002118:Calcium