PPP1R1B
Encyclopedia
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
.
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 (PPP1CA
) inhibitor. 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.
, 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 multiple drugs including cocaine, amphetamine, nicotine, caffeine, LSD, PCP, ethanol and morphine, and in Parkinson's disease
or EPS (Extra-pyramidal symptoms). DARPP-32 levels are decreased in the dorsolateral prefrontal cortex
and lymphocytes of both schizophrenia
and bipolar disorder
patients. This alteration is suggested to be related to the pathology, since 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 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 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.
regulates the expression of DARPP-32. The Akt
and CDK5/p35 intracelular pathway is suggested to be involved on this regulation. Also, neuronal calcium sensor-1
was suggested to modulate the expression of DARPP-32.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the PPP1R1B gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
Midbrain dopaminergic neurons play a critical role in multiple brain functions, and abnormal signaling through dopaminergic pathwaysDopaminergic pathways
Dopaminergic pathways are neural pathways in the brain which transmit the neurotransmitter dopamine from one region of the brain to another.The neurons of the dopaminergic pathways have axons which run the entire length of the pathway...
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
Dopamine receptor D1
Dopamine receptor D1, also known as DRD1, is a protein that in humans is encoded by the DRD1 gene.- Function :This gene encodes the D1 subtype of the dopamine receptor. The D1 subtype is the most abundant dopamine receptor in the central nervous system. This G-protein-coupled receptor stimulates...
. The function of DARPP32 seems to be regulated by receptor stimulation. Both dopaminergic and glutamatergic (NMDA
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
) receptor stimulation regulate the extent of DARPP32 phosphorylation, but in opposite directions. Dopamine D1 receptor stimulation enhances cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
formation, resulting in the phosphorylation of DARPP32; phosphorylated DARPP32 is a potent protein phosphatase-1 (PPP1CA
PPP1CA
Serine/threonine-protein phosphatase PP1-alpha catalytic subunit is an enzyme that in humans is encoded by the PPP1CA gene.-Interactions:...
) inhibitor. NMDA receptor stimulation elevates intracellular calcium, which leads to activation of calcineurin
Calcineurin
Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and calcium-dependent serine-threonine phosphatase, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs...
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 dopamineDopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, glutamate and adenosine; and there is some support for a role of the gene in schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, as well as being involved in the action of multiple drugs including cocaine, amphetamine, nicotine, caffeine, LSD, PCP, ethanol and morphine, and in Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
or EPS (Extra-pyramidal symptoms). DARPP-32 levels are decreased in the dorsolateral prefrontal cortex
Dorsolateral prefrontal cortex
The dorsolateral prefrontal cortex , according to a more restricted definition, is roughly equivalent to Brodmann areas 9 and 46. According to a broader definition DL-PFC consists of the lateral portions of Brodmann areas 9 – 12, of areas 45, 46, and the superior part of area 47. These regions...
and lymphocytes of both schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
patients. This alteration is suggested to be related to the pathology, since 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 phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
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 striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
and the prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
, 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
Brain-derived neurotrophic factorBrain-derived neurotrophic factor
Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF...
regulates the expression of DARPP-32. The Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
and CDK5/p35 intracelular pathway is suggested to be involved on this regulation. Also, neuronal calcium sensor-1
Neuronal calcium sensor-1
Neuronal calcium sensor-1 also known as frequenin homolog is a protein that in humans is encoded by the FREQ gene...
was suggested to modulate the expression of DARPP-32.