TGFβ1 downregulates neurite outgrowth, expression of Ca2+ transporters, and mitochondrial dynamics of in vitro cerebellar granule cells

Neuroreport. 2014 Mar 26;25(5):340-6. doi: 10.1097/WNR.0000000000000106.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Boron Compounds / pharmacology
  • Calcium / metabolism
  • Cell Enlargement
  • Cells, Cultured
  • Central Nervous System Agents / pharmacology
  • Cerebellum / drug effects
  • Cerebellum / physiology*
  • Inositol 1,4,5-Trisphosphate Receptors / antagonists & inhibitors
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mitochondria / physiology*
  • Mitochondrial Dynamics / physiology
  • Neurites / drug effects
  • Neurites / physiology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Pyrazoles / pharmacology
  • Pyrroles / pharmacology
  • Rats
  • Rats, Wistar
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Atp2a2 protein, rat
  • Boron Compounds
  • Central Nervous System Agents
  • ITPR2 protein, rat
  • Inositol 1,4,5-Trisphosphate Receptors
  • Itpr1 protein, rat
  • Ly-364947
  • Pyrazoles
  • Pyrroles
  • Ryanodine Receptor Calcium Release Channel
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta1
  • 2-aminoethoxydiphenyl borate
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium