title: TGFβ1 downregulates neurite outgrowth, expression of Ca2+ transporters, and mitochondrial dynamics of in vitro cerebellar granule cells.
abstract: Acute injury to central nervous system (CNS) triggers neurodegenerative processes that can result in serious damage or complete loss of function. After injury, production of transforming growth factor β1 (TGFβ1) increases and initiates creation of a fibrotic scar that prevents normal growth, plasticity, and recovery of damaged neurons. Administration of TGFβ1 antagonists can prevent its pathological effects. To define consequences of increased TGFβ1 release on calcium signaling, neuronal plasticity, excitability, and mitochondrial dynamics in CNS neurons we directly exposed a rat primary culture of cerebellar granule neurons to TGFβ1. We focused on changes in expression of intracellular calcium transporters, especially inositol-1,4,5-trisphosphate receptor (IP3R) type 1, mitochondrial dynamics, and membrane excitability. TGFβ1 significantly decreased the gene and protein expression of inositol-1,4,5-trisphosphate receptor type 1 and the gene expression of additional intracellular Ca transporters such as IP3R2, ryanodine receptor type 1 (RyR1), RyR2, and SERCA2. Altered calcium signaling suppressed neurite outgrowth and significantly decreased the length of the mitochondria and the frequency of mitochondrial fusion. The resting membrane potential of cerebellar granule neurons was hyperpolarized and slow after depolarization of single action potential was suppressed. LY364947, a blocker of TGFβ1 receptor I, prevented these effects, and IP3 receptor blocker 2-aminoethoxydiphenyl borate (2APB) mimicked them. After CNS injury TGFβ1 downregulates intracellular Ca levels and alters Ca signaling within injured neurons. We suggest that in our model TGFβ1 may trigger both neurodegenerative and neuroprotective events through IP3-induced Ca signaling.
authors.affiliation: aInstitute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia bDepartment of Pharmacology, Faculty of Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Jaskova
authors.forename: Michaela
authors.initials: M
authors.lastname: Pavlovicova
authors.forename: Michal
authors.initials: M
authors.lastname: Cagalinec
authors.forename: Lubica
authors.initials: L
authors.lastname: Lacinova
authors.forename: Dana
authors.initials: D
authors.lastname: Jurkovicova
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D049108:Cell Enlargement; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D063154:Mitochondrial Dynamics / Q000502:physiology; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D011804:Quinolines
chemical_list: D001896:Boron Compounds; D002118:Calcium; D002491:Central Nervous System Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011720:Pyrazoles; D011758:Pyrroles; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D053773:Transforming Growth Factor beta1; C506948:Atp2a2 protein, rat; C506615:HTS 466284; D011804:Quinolines; C506928:ITPR2 protein, rat; C488910:Itpr1 protein, rat; C508962:Tgfb1 protein, rat; C109986:2-aminoethoxydiphenyl borate