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- Title
Downregulation of the cAMP/PKA pathway in PC12 cells overexpressing NCS-1.
- Authors
Souza, Bruno R; Torres, Karen C L; Miranda, Débora M; Motta, Bernardo S; Caetano, Fernando S; Rosa, Daniela V F; Souza, Renan P; Giovani, Antônio, Jr; Carneiro, Daniel S; Guimarães, Melissa M; Martins-Silva, Cristina; Reis, Helton J; Gomez, Marcus V; Jeromin, Andreas; Romano-Silva, Marco A
- Abstract
It is well known that dopamine imbalances are associated with many psychiatric disorders and that the dopaminergic receptor D₂ is the main target of antipsychotics. Recently it was shown that levels of two proteins implicated in dopaminergic signaling, Neuronal calcium sensor-1 (NCS-1) and DARPP-32, are altered in the prefrontal cortex (PFC) of both schizophrenic and bipolar disorder patients. NCS-1, which inhibits D₂ internalization, is upregulated in the PFC of both patients. DARPP-32, which is a downstream effector of dopamine signaling, integrates the pathways of several neurotransmitters and is downregulated in the PFC of both patients. Here, we used PC12 cells stably overexpressing NCS-1 (PC12-NCS-1 cells) to address the function of this protein in DARPP-32 signaling pathway in vitro. PC12-NCS-1 cells displayed downregulation of the cAMP/PKA pathway, with decreased levels of cAMP and phosphorylation of CREB at Ser133. We also observed decreased levels of total and phosphorylated DARPP-32 at Thr34. However, these cells did not show alterations in the levels of D₂ and phosphorylation of DARPP-32 at Thr75. These results indicate that NCS-1 modulates PKA/cAMP signaling pathway. Identification of the cellular mechanisms linking NCS-1 and DARPP-32 may help in the understanding the signaling machinery with potential to be turned into targets for the treatment of schizophrenia and other debilitating psychiatric disorders.
- Publication
Cellular and molecular neurobiology, 2011, Vol 31, Issue 1, p135
- ISSN
1573-6830
- Publication type
Journal Article
- DOI
10.1007/s10571-010-9562-4