PPP1R1B

Protein phosphatase 1 regulatory subunit 1B (PPP1R1B), also known as dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32), is a is_associated_with::protein that in humans is encoded by the PPP1R1B is_associated_with::gene.

Function
Midbrain dopaminergic neurons play a critical role in multiple brain functions, and abnormal signaling through is_associated_with::dopaminergic pathways has been implicated in several major neurologic and psychiatric disorders. One well-studied target for the actions of dopamine is DARPP32. In the densely dopamine- and glutamate-innervated rat caudate-putamen, DARPP32 is expressed in medium-sized spiny neurons that also express dopamine D1 receptors. The function of DARPP32 seems to be regulated by receptor stimulation. Both dopaminergic and glutamatergic (NMDA) receptor stimulation regulate the extent of DARPP32 phosphorylation, but in opposite directions. Dopamine D1 receptor stimulation enhances cAMP formation, resulting in the phosphorylation of DARPP32; phosphorylated DARPP32 is a potent protein phosphatase-1 (is_associated_with::PPP1CA) inhibitor. NMDA receptor stimulation elevates intracellular calcium, which leads to activation of is_associated_with::calcineurin and dephosphorylation of phospho-DARPP32, thereby reducing the phosphatase-1 inhibitory activity of DARPP32.

Clinical significance
This gene is also known as DARPP-32, highlighting its role as a dopamine- and cyclic AMP-regulated phosphoprotein. As such PPP1R1B affects is_associated_with::dopamine, is_associated_with::glutamate and is_associated_with::adenosine; and there is some support for a role of the gene in is_associated_with::schizophrenia, as well as being involved in the action of drugs including cocaine, amphetamine, nicotine, LSD, caffeine, PCP, ethanol and morphine, and in is_associated_with::Parkinson's disease or EPS (Extra-pyramidal symptoms). DARPP-32 levels are decreased in the is_associated_with::dorsolateral prefrontal cortex and is_associated_with::lymphocytes of both is_associated_with::schizophrenia and is_associated_with::bipolar disorder patients. This alteration is suggested to be related to the pathology, since is_associated_with::antipsychotics do not regulate the expression of DARPP-32.

A considerable proportion of the psychomotor effects of cannabinoids can be accounted for by a signaling cascade in striatal projection neurons involving PKA-dependent is_associated_with::phosphorylation of DARPP-32, achieved via modulation of dopamine D2 and adenosine A2A transmission.

PPP1R1B has also been associated with improved transfer of information between the is_associated_with::striatum and the is_associated_with::prefrontal cortex, suggesting that variants of PPP1R1B can in some circumstances lead to improved and more flexible cognition, while, in the presence of other genetic and environmental factors, it may lead to symptoms of schizophrenia.

Regulation
is_associated_with::Brain-derived neurotrophic factor regulates the expression of DARPP-32. The is_associated_with::Akt and CDK5/p35 intracelular pathway is suggested to be involved on this regulation. Also, is_associated_with::neuronal calcium sensor-1 was suggested to modulate the expression of DARPP-32.

Discovery
PPP1R1B was discovered by is_associated_with::Paul Greengard and his co-workers.