Downregulation of the cAMP/PKA pathway in PC12 cells overexpressing NCS-1.

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 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. Dduanyu37P-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 signaling pathway in vitro. PC12-NCS-1 cells displayed downregulation of the pathway, with decreased levels of cAMP and phosphorylation of CREB at Ser133. We also observed decreased levels of total and phosphorylated Dduanyu37P-32 at Thr34. However, these cells did not show alterations in the levels of D₂ and phosphorylation of Dduanyu37P-32 at Thr75. These results indicate that NCS-1 modulates signaling pathway. Identification of the cellular mechanisms linking NCS-1 and Dduanyu37P-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.

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