Naslov
Disrupted-In-Schizophrenia 1 (DISC1) and Protein Kinase A signalling

Autori
Bradshaw, Nick ; Mackie, Shaun ; Christie, Sheila ; Porteous, David ; Millar, Kirsty

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Skup
British Neuroscience Association Meeting 2007

Mjesto i datum
Harrogate, Ujedinjeno Kraljevstvo, 02.04.2007

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
DISC1, PKA, PDE4, schizophrenia

Sažetak
Disrupted-In-Schizophrenia 1 (DISC1) is a widely accepted risk factor for schizophrenia and related psychiatric disorders. We have previously demonstrated that DISC1 interacts with phosphodiesterase 4B (PDE4B), an independently identified risk factor for psychiatric illness. Type 4 phosphodiesterases are of interest because they are homologous to the Drosophila learning and memory mutant Dunce, consistent with the cognitive deficits that characterise schizophrenia. Moreover PDE4s are specifically inhibited by the prototypic antidepressant rolipram, and PDE4-deficient mice behave as if on antidepressants. PDE4B hydrolyses cAMP, a key signalling molecule in the Protein Kinase A (PKA) pathway. PDE4B cAMP hydrolysing activity is regulated by PKA phosphorylation, forming a negative feedback loop. Intriguingly, PDE4B binding to DISC1 is dynamic and cAMP-dependent, suggesting that DISC1 sequesters PDE4B in a low activity state until cAMP hydrolysing activity is required to switch off cAMP signalling, at which time PDE4B is released. We now demonstrate that DISC1 is also phosphorylated by PKA in vivo, suggesting that DISC1 function may be modulated indirectly by PDE4B. This interaction and potential for regulation of two independently identified genetic risk factors for psychiatric illness implies that they are key to psychosis-related molecular pathways.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti, Biotehnologija

POVEZANOST RADA