Faces of DARPP-32: Master Signaling Mediator in the Brain?

As a major target for dopamine-activated adenylyl cyclase and protein kinase A in the striatum, DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission and can act either as a phosphatase or kinase inhibitor in a contextually dependent manner. Growing evidence points to DARPP-32 as a key mediator/modulator in numerous signal transduction cascades implicated in a growing number of neurological disorders such as schizophrenia and depression, as well as in drug abuse and addiction. For example, it has been shown that acute exposure of mice to cocaine increases phosphorylation of DARPP-32 at Thr34 with a concommitment decrease in phosphorylation at Thr75, whereas chronic exposure leads to a reversal of this phospho profile. It has also been observed that many schizophrenic patients show decreased levels of DARPP-32 in the prefrontal cortex.

While the precise role that DARPP-32 plays in these psychiatric disorders is still being elucidated, the existing body of literature clearly portrays DARPP-32 as playing a central role in multiple signaling pathways. Further research will determine neuronal subpopulations where phosphorylation of DARPP-32 occurs as well as the functional importance of previously identified phospho sites of DARPP-32.

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