Protein phosphatase 1 regulatory subunit 1B (PPP1R1B), also known as dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32), is a protein that in humans is encoded by the PPP1R1B gene. [5] [6]
Protein phosphatase 1 regulatory subunit 1B (PPP1R1B), also known as dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32), is a protein that in humans is encoded by the PPP1R1B gene. [5] [6]
Midbrain dopaminergic neurons play a critical role in multiple brain functions, and abnormal signaling through 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 [7] that also express dopamine D1 receptors. [8] 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. [9] Dopamine D1 receptor stimulation enhances cAMP formation, resulting in the phosphorylation of DARPP32; [8] (this is disputed by more recent research that claims cAMP signaling induces dephosphorylation of DARPP32 [10] ) phosphorylated DARPP32 is a potent protein phosphatase-1 (PPP1CA) inhibitor. [11] NMDA receptor stimulation elevates intracellular calcium, which leads to activation of calcineurin and dephosphorylation of phospho-DARPP32, thereby reducing the phosphatase-1 inhibitory activity of DARPP32. [5] [9] DARPP-32 is critical for dopamine dependent striatal synaptic plasticity, [12] possibly by serving as a dopamine-dependent gating mechanism for calcium/CaMKII signaling. [13] It has been predicted that DARPP-32, in conjunction with ARPP-21, could also be involved in setting-up of eligibility trace-like temporal window for striatal postsynaptic signaling. [13]
This gene is also known as DARPP-32, highlighting its role as a dopamine- and cyclic AMP-regulated phosphoprotein. As such PPP1R1B affects dopamine, [14] glutamate and adenosine; and there is some support for a role of the gene in schizophrenia, as well as being involved in the action of drugs including cocaine, amphetamine, nicotine, LSD, caffeine, PCP, ethanol and morphine, [15] and in Parkinson's disease or EPS (Extra-pyramidal symptoms). [16] DARPP-32 levels are decreased in the dorsolateral prefrontal cortex and lymphocytes of both schizophrenia and bipolar disorder patients. [17] [18] [19] This alteration is suggested to be related to the pathology, since antipsychotics do not regulate the expression of DARPP-32. [20] [21]
A considerable proportion of the psychomotor effects of cannabinoids can be accounted for by a signaling cascade in striatal projection neurons involving PKA-dependent phosphorylation of DARPP-32, achieved via modulation of dopamine D2 and adenosine A2A transmission. [22]
PPP1R1B has also been associated with improved transfer of information between the striatum and the 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. [23]
There are two protein products encoded by PPP1R1B: DARPP-32 and t-Darpp. t-Darpp is a truncated version of DARPP-32 as it is missing the first 36 amino acids at the N-terminus. [24] Both isoforms are overexpressed in a number of cancers including those derived from gastric, colon, prostate, esophageal, breast, and lung tissues. [25] [26] In Her-2-positive breast cancer cells, t-Darpp overexpression imparts resistance to Trastuzumab (Herceptin), the chemotherapy drug that shuts down the Her-2 signaling pathway. [27] [28] [29]
Brain-derived neurotrophic factor regulates the expression of DARPP-32. [30] The Akt and CDK5/p35 intracellular pathway is suggested to be involved on this regulation. [31] Also, neuronal calcium sensor-1 was suggested to modulate the expression of DARPP-32. [32]
PPP1R1B was discovered by Paul Greengard and his co-workers. [6]
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle.
The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.
The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum in the forebrain. It is one of the four major dopamine pathways in the brain, and is critical in the production of movement as part of a system called the basal ganglia motor loop. Dopaminergic neurons of this pathway release dopamine from axon terminals that synapse onto GABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), located in the striatum.
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.
The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.
Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins:
Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of GABAergic inhibitory cell representing 95% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary phenotypes : D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway. Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.
A heteromer is something that consists of different parts; the antonym of homomeric. Examples are:
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.
Dopamine receptor D5, also known as D1BR, is a protein that in humans is encoded by the DRD5 gene. It belongs to the D1-like receptor family along with the D1 receptor subtype.
cAMP-regulated phosphoprotein 19 is a protein that in humans is encoded by the ARPP19 gene.
Cyclic AMP-regulated phosphoprotein, 21 kD, also known as ARPP-21, is a human gene.
Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.
SR-142948 is a drug used in scientific research which is a non-peptide antagonist selective for the neurotensin receptors, although not selective between subtypes.
A-77636 is a synthetic drug which acts as a selective D1 receptor full agonist. It has nootropic, anorectic, rewarding and antiparkinsonian effects in animal studies, but its high potency and long duration of action causes D1 receptor downregulation and tachyphylaxis, and unlike other D1 full agonists such as SKF-82,958, it does not produce place preference in animals. A-77636 partially substituted for cocaine in animal studies, and has been suggested for use as a possible substitute drug in treating addiction, but it is better known for its use in studying the role of D1 receptors in the brain.
Synapsin I, is the collective name for Synapsin Ia and Synapsin Ib, two nearly identical phosphoproteins that in humans are encoded by the SYN1 gene. In its phosphorylated form, Synapsin I may also be referred to as phosphosynaspin I. Synapsin I is the first of the proteins in the synapsin family of phosphoproteins in the synaptic vesicles present in the central and peripheral nervous systems. Synapsin Ia and Ib are close in length and almost the same in make up, however, Synapsin Ib stops short of the last segment of the C-terminal in the amino acid sequence found in Synapsin Ia.
Synapsin II is the collective name for synapsin IIa and synapsin IIb, two nearly identical phosphoproteins in the synapsin family that in humans are encoded by the SYN2 gene. Synapsins associate as endogenous substrates to the surface of synaptic vesicles and act as key modulators in neurotransmitter release across the presynaptic membrane of axonal neurons in the nervous system.
A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.
The D1–D2 dopamine receptor heteromer is a receptor heteromer consisting of D1 and D2 protomers.
