Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dopamine (DA) innervation of medial prefrontal cortex (mPFC) regulates cognitive activity in a complex manner. Alterations of DA function, particularly via the DA D1 receptor class (D1R), are implicated in both schizophrenia and drug addiction, yet the precise roles of DA in modulating mPFC excitability remain unclear. We focused on DA modulation of voltage-gated K(+) current (VGKC) in acutely dissociated rat mPFC pyramidal neurons. We defined three components of the whole-cell VGKC according to biophysical and pharmacological properties. The A-type current (I(A)), with rapid activation and inactivation kinetics, was completely inactivated by prolonged holding of the membrane potential at -40 mV and was sensitive to the K(+) channel blocker 4-aminopyridine (4-AP) but not tetraethylammonium (TEA) or dendrotoxin (DTX). The slowly inactivating K(+) current (I(D)), with rapid activation but relatively slow inactivation, was the major contributor to VGKC and was completely inactivated at -40 mV and sensitive to TEA and DTX but less so to 4-AP. The very slowly inactivating K(+) current (I(K)) was elicited by command steps to more depolarized potentials from a prolonged holding potential of -40 mV and was sensitive to all three blockers. Stimulation of DA D2 receptors failed to alter any component of whole-cell VGKC. Stimulation of DA D1Rs selectively suppressed I(D), an effect mimicked by the adenylyl cyclase activator forskolin, the active cAMP analog Sp-cAMP, and the protein phosphatase inhibitor okadaic acid. Inhibition of protein kinase A (PKA) with either PKI or Rp-cAMP abolished D1R modulation. Thus, the DA D1R/cAMP/PKA signaling pathway mediates modulation of I(D) by DA in rat mPFC pyramidal neurons.
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PMID:Dopamine D1-class receptors selectively modulate a slowly inactivating potassium current in rat medial prefrontal cortex pyramidal neurons. 1268 54

Receptor-mediated dopamine (DA) modulation of neuronal excitability in the nucleus accumbens (NAc) has been shown to be critically involved in drug addiction and a variety of brain diseases. However, the mechanisms underlying the physiological or pathological molecular process of DA modulation remain largely elusive. Here, we demonstrate that stimulation of DA D2 class receptors (D2R) enhanced voltage-sensitive sodium currents (VSSCs, I(Na)) in freshly dissociated NAc neurons via suppressing tonic activity of the cyclic AMP/PKA cascade and facilitating intracellular Ca2+ signaling. D2R-mediated I(Na) enhancement depended on activation of G(i/o) proteins and was mimicked by direct inhibition of PKA. Furthermore, increasing free [Ca2+]in by activating inositol 1,4,5-triphosphate receptors (IP3Rs), blocking Ca2+ reuptake, or adding buffered Ca2+, all enhanced I(Na). Under these circumstances, D2R-mediated I(Na) enhancement was occluded. In contrast, D2R-mediated I(Na) enhancement was blocked by inhibition of IP3Rs, chelation of free Ca2+, or inhibition of Ca2(+)/calmodulin-activated calcineurin (CaN), but not by inhibition of phospholipase C (PLC). Although stimulation of muscarinic cholinergic receptors (mAChRs) also increased I(Na), this action was blocked by PLC inhibitors. Our findings indicate that D2Rs mediate an enhancement of VSSCs in NAc neurons, in which cytosolic free Ca2+ plays a crucial role. Our results also suggest that D2R-mediated reduction in tonic PKA activity may increase free [Ca2+]in, primarily via disinhibition of IP3Rs. IP3R activation then facilitates Ca2+ signaling and subsequently enhances VSSCs via decreasing PKA-induced phosphorylation and increasing CaN-induced dephosphorylation of Na+ channels. This study provides insight into the complex and dynamic role of D2Rs in the NAc.
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PMID:Dopamine D2 receptor-activated Ca2+ signaling modulates voltage-sensitive sodium currents in rat nucleus accumbens neurons. 1559 Jul 33

It has recently emerged that there is a commonality in the molecular mechanisms underlying long-term neuronal changes in drug addiction and those mediating synaptic plasticity associated with learning and memory. In the hippocampus, the calcium-calmodulin-dependent protein phosphatase calcineurin plays a pivotal role in the molecular mechanisms that underlie learning and memory functions. Transgenic mice that express an active form of calcineurin specifically in forebrain structures have previously been shown to have a deficit in the transition from short- to long-term memory. Here, we investigated the involvement of calcineurin in the motivational effects of amphetamine and morphine using this line of transgenic mice (CN98). Our results showed that amphetamine and morphine did not induce conditioned place preference in calcineurin-mutant mice, whereas food remained an efficient reinforcer. In addition, behavioural sensitization to these two drugs, as measured by horizontal locomotion, was disturbed in the transgenic mice. In contrast, neither the horizontal locomotion in response to acute D-amphetamine or morphine nor the somatic signs of morphine withdrawal were affected in calcineurin mutant mice compared to their wild-type littermates. Our data indicate that calcineurin-mediated protein dephosphorylation in the hippocampus is involved in the long-term effects of drugs of abuse without influencing the motivational response to a natural reward or the physical component of opioid withdrawal. The present results emphasize the essential role of hippocampal-dependent learning and memory in the development of drug addiction.
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PMID:The reinforcing effects of chronic D-amphetamine and morphine are impaired in a line of memory-deficient mice overexpressing calcineurin. 1597 18

The widespread distribution of the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) in the adult brain suggests its role in a broad range of brain functions. Here we show evidence supporting a physical interaction of PTEN with a region in the third intracellular loop (3L4F) of the serotonin 5-HT2C receptor (5-HT2cR, formerly 5-HT1c receptor) in cell cultures. PTEN limits agonist-induced phosphorylation of 5-HT2cR through its protein phosphatase activity. We showed the probable existence of PTEN:5-HT2cR complexes in putative dopaminergic neurons in the rat ventral tegmental area (VTA), a brain region in which virtually all abused drugs exert rewarding effects by activating its dopamine neurons. We synthesized the interfering peptide Tat-3L4F, which is able to disrupt PTEN coupling with 5-HT2cR. Systemic application of Tat-3L4F or the 5-HT2cR agonist Ro600175 suppressed the increased firing rate of VTA dopaminergic neurons induced by delta9-tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana. Using behavioral tests, we found that Tat-3L4F or Ro600175 blocks conditioned place preference of THC or nicotine, and that Ro600175, but not Tat-3L4F, produces anxiogenic effects, penile erection, hypophagia and motor functional suppression. These results suggest a potential strategy for treating drug addiction with the Tat-3L4F peptide.
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PMID:Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse. 1652 Jul 73

It has recently emerged that there is a commonality in the molecular mechanisms underlying long-term neuronal changes in drug addiction and those mediating synaptic plasticity associated with learning and memory. Several lines of evidence indicate that the brain regions involved in learning and memory and those underlying drug addiction may overlap. Learning and memory processes and drug addiction also share intracellular signaling cascades and are associated with similar changes in synaptic plasticity. The purpose of the present paper is an attempt to further explore the hypothesis that learning and memory are essential for the development of addiction. The data suggest that hippocampal calcineurin signaling is involved in the long-term adaptation after chronic drug treatment in a way that may parallel its role during memory formation. Such an effect is consistent with the common molecular mechanisms shared by addiction and memory processes. Given the well-established role of the hippocampus in associative learning and memory, this paper further emphasize the important role of this forebrain structure in controlling long-lasting features of addiction.
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PMID:[Memory processes and addiction: involvement of the calcineurin signaling pathway]. 1750 67

Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.
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PMID:A phosphatase cascade by which rewarding stimuli control nucleosomal response. 1849 28

Drugs of abuse induce neuroadaptations through regulation of gene expression. Although much attention has focused on transcription factor activities, new concepts have recently emerged on the role of chromatin remodelling as a prerequisite for regulation of gene expression in neurons. Thus, for transcription to occur, chromatin must be decondensed, a dynamic process that depends on post-translational modifications of histones. We review here these modifications with a particular emphasis on the role of histone H3 phosphorylation at the promoter of specific genes, including c-fos and c-jun. We trace the signalling pathways involved in H3 phosphorylation and provide evidence for a role of mitogen and stress-activated protein kinase-1 (MSK1) downstream from the MAPK/extracellular-signal regulated kinase (ERK) cascade. In response to cocaine, MSK1 controls an early phase of histone H3 phosphorylation at the c-fos promoter in striatal neurons. MSK1 action may be potentiated by the concomitant inhibition of protein phosphatase 1 by nuclear translocation of dopamine- and cAMP-regulated phosphoprotein Mr = 32 000. H3 phosphorylation by MSK1 is critically involved in c-fos transcription, and cocaine-induced locomotor sensitization. Thus, ERK plays a dual role in gene regulation and drug addiction by direct activation of transcription factors and by chromatin remodelling.
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PMID:Role of the ERK/MSK1 signalling pathway in chromatin remodelling and brain responses to drugs of abuse. 1918 68

The 32-kDa dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein (DARPP-32) is recognized to be critical to the pathogenesis of drug addiction. Opiates via the mu-receptor act on the dopaminergic system in the brain and modulates the expression of DARPP-32 phosphoprotein which is an important mediator of the activity of the extracellular signal-regulated kinase (ERK) signaling cascades, the activation of which represents an exciting nexus for drug-induced changes in neural long-term synaptic plasticity. Silencing of DARPP-32 using an siRNA against DARPP-32 may provide a novel gene therapy strategy to overcome drug addiction. In this study, we investigated the effect of the opiate (heroin) on D1 receptor (D1R) and DARPP-32 expression and additionally, evaluated the effects of DARPP-32-siRNA gene silencing on protein phosphatase-1 (PP-1), ERK, and cAMP response element-binding (CREB) gene expression in primary normal human astrocytes (NHA) cells in vitro. Our results indicate that heroin significantly upregulated both D1R and DARPP-32 gene expression, and that DARPP-32 silencing in the NHA cells resulted in the significant modulation of the activity of downstream effector molecules such as PP-1, ERK, and CREB which are known to play an important role in opiate abuse-induced changes in long-term neural plasticity. These findings have the potential to facilitate the development of DARPP32 siRNA-based therapeutics against drug addiction.
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PMID:Therapeutic targeting of "DARPP-32": a key signaling molecule in the dopiminergic pathway for the treatment of opiate addiction. 1989 79

Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction.
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PMID:A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity. 2016 76

Plasticity at excitatory glutamatergic synapses in the central nervous system is believed to be critical for neuronal circuits to process and encode information, allowing animals to perform complex behaviors such as learning and memory. In addition, alterations in synaptic plasticity are associated with human diseases, including Alzheimer disease, epilepsy, chronic pain, drug addiction, and schizophrenia. Long-term potentiation (LTP) and depression (LTD) in the hippocampal region of the brain are two forms of synaptic plasticity that increase or decrease, respectively, the strength of synaptic transmission by postsynaptic AMPA-type glutamate receptors. Both LTP and LTD are induced by activation of NMDA-type glutamate receptors but differ in the level and duration of Ca(2+) influx through the NMDA receptor and the subsequent engagement of downstream signaling by protein kinases, including PKA, PKC, and CaMKII, and phosphatases, including PP1 and calcineurin-PP2B (CaN). This review addresses the important emerging roles of the A-kinase anchoring protein family of scaffold proteins in regulating localization of PKA and other kinases and phosphatases to postsynaptic multiprotein complexes that control NMDA and AMPA receptor function during LTP and LTD.
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PMID:AKAP signaling complexes in regulation of excitatory synaptic plasticity. 2149 12


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