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As quantum circuits become more integrated and complex, additional error sources that were previously insignificant start to emerge. Consequently, the fidelity of quantum gates benchmarked under pristine conditions falls short of predicting their performance in realistic circuits. To overcome this problem, we must improve their robustness against pertinent error models besides isolated fidelity. Here, we report the experimental realization of robust quantum gates in superconducting quantum circuits based on a geometric framework for diagnosing and correcting various gate errors. Using quantum process tomography and randomized benchmarking, we demonstrate robust single-qubit gates against quasistatic noise and spatially correlated noise in a broad range of strengths, which are common sources of coherent errors in large-scale quantum circuits. We also apply our method to nonstatic noises and to realize robust two-qubit gates. Our Letter provides a versatile toolbox for achieving noise-resilient complex quantum circuits.
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Anyons, exotic quasiparticles in two-dimensional space exhibiting nontrivial exchange statistics, play a crucial role in universal topological quantum computing. One notable proposal to manifest the fractional statistics of anyons is the toric code model; however, scaling up its size through quantum simulation poses a serious challenge because of its highly entangled ground state. In this Letter, we demonstrate that a modular superconducting quantum processor enables hardware-pragmatic implementation of the toric code model. Through in-parallel control across separate modules, we generate a 10-qubit toric code ground state in four steps and realize six distinct braiding paths to benchmark the performance of anyonic statistics. The path independence of the anyonic braiding statistics is verified by correlation measurements in an efficient and scalable fashion. Our modular approach, serving as a hardware embodiment of the toric code model, offers a promising avenue toward scalable simulation of topological phases, paving the way for quantum simulation in a distributed fashion.
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Gate-based quantum computation has been extensively investigated using quantum circuits based on qubits. In many cases, such qubits are actually made out of multilevel systems but with only two states being used for computational purpose. While such a strategy has the advantage of being in line with the common binary logic, it in some sense wastes the ready-for-use resources in the large Hilbert space of these intrinsic multidimensional systems. Quantum computation beyond qubits (e.g., using qutrits or qudits) has thus been discussed and argued to be more efficient than its qubit counterpart in certain scenarios. However, one of the essential elements for qutrit-based quantum computation, two-qutrit quantum gate, remains a major challenge. In this Letter, we propose and demonstrate a highly efficient and scalable two-qutrit quantum gate in superconducting quantum circuits. Using a tunable coupler to control the cross-Kerr coupling between two qutrits, our scheme realizes a two-qutrit conditional phase gate with fidelity 89.3% by combining simple pulses applied to the coupler with single-qutrit operations. We further use such a two-qutrit gate to prepare an EPR state of two qutrits with a fidelity of 95.5%. Our scheme takes advantage of a tunable qutrit-qutrit coupling with a large on:off ratio. It therefore offers both high efficiency and low crosstalk between qutrits, thus being friendly for scaling up. Our Letter constitutes an important step toward scalable qutrit-based quantum computation.
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Unwanted ZZ interaction is a quantum-mechanical crosstalk phenomenon which correlates qubit dynamics and is ubiquitous in superconducting qubit systems. It adversely affects the quality of quantum operations and can be detrimental in scalable quantum information processing. Here we propose and experimentally demonstrate a practically extensible approach for complete cancellation of residual ZZ interaction between fixed-frequency transmon qubits, which are known for long coherence and simple control. We apply to the intermediate coupler that connects the qubits a weak microwave drive at a properly chosen frequency in order to noninvasively induce an ac Stark shift for ZZ cancellation. We verify the cancellation performance by measuring vanishing two-qubit entangling phases and ZZ correlations. In addition, we implement a randomized benchmarking experiment to extract the idling gate fidelity which shows good agreement with the coherence limit, demonstrating the effectiveness of ZZ cancellation. Our method allows independent addressability of each qubit-qubit connection and is applicable to both nontunable and tunable couplers, promising better compatibility with future large-scale quantum processors.
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For building a scalable quantum processor with superconducting qubits, ZZ interaction is of great concern because its residual has a crucial impact to two-qubit gate fidelity. Two-qubit gates with fidelity meeting the criterion of fault-tolerant quantum computation have been demonstrated using ZZ interaction. However, as the performance of quantum processors improves, the residual static ZZ can become a performance-limiting factor for quantum gate operation and quantum error correction. Here, we introduce a superconducting architecture using qubits with opposite-sign anharmonicity, a transmon qubit, and a C-shunt flux qubit, to address this issue. We theoretically demonstrate that by coupling the two types of qubits, the high-contrast ZZ interaction can be realized. Thus, we can control the interaction with a high on-off ratio to implement two-qubit controlled-Z gates, or suppress it during two-qubit gate operation using XY interaction (e.g., an iSWAP gate). The proposed architecture can also be scaled up to multiqubit cases. In a fixed coupled system, ZZ crosstalk related to neighboring spectator qubits could also be heavily suppressed.
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High-quality two-qubit gate operations are crucial for scalable quantum information processing. Often, the gate fidelity is compromised when the system becomes more integrated. Therefore, a low-error-rate, easy-to-scale two-qubit gate scheme is highly desirable. Here, we experimentally demonstrate a new two-qubit gate scheme that exploits fixed-frequency qubits and a tunable coupler in a superconducting quantum circuit. The scheme requires less control lines, reduces cross talk effect, and simplifies calibration procedures, yet produces a controlled-Z gate in 30 ns with a high fidelity of 99.5%, derived from the interleaved randomized benchmarking method. Error analysis shows that gate errors are mostly coherence limited. Our demonstration paves the way for large-scale implementation of high-fidelity quantum operations.
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A Berry curvature is an imaginary component of the quantum geometric tensor (QGT) and is well studied in many branches of modern physics; however, the quantum metric as a real component of the QGT is less explored. Here, by using tunable superconducting circuits, we experimentally demonstrate two methods to directly measure the quantum metric tensor for characterizing the geometry and topology of underlying quantum states in parameter space. The first method is to probe the transition probability after a sudden quench, and the second one is to detect the excitation rate under weak periodic driving. Furthermore, based on quantum metric and Berry-curvature measurements, we explore a topological phase transition in a simulated time-reversal-symmetric system. The work opens up a unique approach to explore the topology of quantum states with the QGT.
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This corrects the article DOI: 10.1103/PhysRevLett.122.210401.
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Tellurene is a new member of the two-dimensional (2D) materials' family, whose existence has been recently confirmed by first principles calculation and experimental work. Tellurene is also the first 2D mono-elemental material of group-VI predicted by scientists, and investigations of its basic properties are still in their infancy. In this study, we use first principles calculation based on density functional theory to investigate the adsorption of nineteen typical adatoms (Li, Na, K, Ca, Fe, Co, Ni, Cu, Zn, Ag, Au, Pd, Pt, B, N, O, Si, Cl, and Al), and five typical gas molecules (H2, O2, H2O, NO2, and NH3) on α-phase as well as ß-phase tellurene sheets. Our calculations shows that most adatoms are chemisorbed on tellurene sheets with large adsorption energies. Moreover, some of the adatoms are observed to give rise to distinct structural deformations and even local reconstructions. We report that a variety of electronic states are induced by the adatoms, which implies that different electronic structures can be engineered by the adsorption of adatoms. In fact, n-type doping, p-type doping, half-metal, and spin-gapless semiconductor features can be acquired by doping adatoms on tellurene sheets. Our calculations also show that the five gas molecules are all physisorbed on tellurene sheets, and no splitting behaviors are observed. Therefore, the adsorption of the five gas molecules has a weak effect on the electronic properties of tellurene. To conclude, our results indicate that adatom engineering may be used to greatly expand the potential applications of 2D tellurene.
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Supraphysiological mechanical stretching in smooth muscle results in decreased contractile activity. However, the mechanism is unclear. Previous studies indicated that intestinal motility dysfunction after edema development is associated with increased smooth muscle stress and decreased myosin light chain (MLC) phosphorylation in vivo, providing an ideal model for studying mechanical stress-mediated decrease in smooth muscle contraction. Primary human intestinal smooth muscle cells (hISMCs) were subjected to either control cyclical stretch (CCS) or edema (increasing) cyclical stretch (ECS), mimicking the biophysical forces in non-edematous and edematous intestinal smooth muscle in vivo. ECS induced significant decreases in phosphorylation of MLC and MLC phosphatase targeting subunit (MYPT1) and a significant increase in p21-activated kinase (PAK) activity compared with CCS. PAK regulated MLC phosphorylation in an activity-dependent biphasic manner. PAK activation increased MLC and MYPT1 phosphorylation in CCS but decreased MLC and MYPT1 phosphorylation in hISMCs subjected to ECS. PAK inhibition had the opposite results. siRNA studies showed that PAK1 plays a critical role in regulating MLC phosphorylation in hISMCs. PAK1 enhanced MLC phosphorylation via phosphorylating MYPT1 on Thr-696, whereas PAK1 inhibited MLC phosphorylation via decreasing MYPT1 on both Thr-696 and Thr-853. Importantly, in vivo data indicated that PAK activity increased in edematous tissue, and inhibition of PAK in edematous intestine improved intestinal motility. We conclude that PAK1 positively regulates MLC phosphorylation in intestinal smooth muscle through increasing inhibitory phosphorylation of MYPT1 under physiologic conditions, whereas PAK1 negatively regulates MLC phosphorylation via inhibiting MYPT1 phosphorylation when PAK activity is increased under pathologic conditions.
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Motilidad Gastrointestinal , Intestinos/fisiología , Músculo Liso/fisiología , Cadenas Ligeras de Miosina/metabolismo , Quinasas p21 Activadas/metabolismo , Animales , Células Cultivadas , Humanos , Masculino , Contracción Muscular , Fosforilación , Ratas , Ratas Sprague-DawleyRESUMEN
Considering that the genotypes of CYP2C19 and MDRI C3435T are two major factors attributed to the inter-individual pharmacokinetic variability of lansoprazole (LSZ), the aim of the study was to simultaneously elucidate the effects of CYP2C19 and MDRI C3435T polymorphisms on the pharmacokinetics difference of LSZ and its metabolites 5'-hydroxy lansoprazole (HLSZ) and lansoprazole sulphone (LSZS) following oral administration of LSZ tablets in healthy Chinese subjects. Plasma concentration of LSZ, HLSZ and LSZS were quantified by a sensitive and specific LC-MS/MS method, while the genotypes of CYP2C19 and MDRI C3435T for each subject were identified by a direct sequencing method. Statistical analysis was performed in the pharmacokinetic parameters including Cmax, t1/2, Tmax, MRTo_-, AUCO-2 and AUCo_r among different genotype groups of CYP2C 19 and MDRI C3435T. Compared to the CYP2Cl9 EMs, the CYP2C 19 PM group showed slower elimination and betteroral bioavailability of LSZ, much higher plasma concentrations of LSZS and lower concentrations of HLSZ with statistically significance. Despite a tendency of more favorable absorption and rapid elimination of LSZ in wild genotype, no significant pharmacokinetics difference was observed between the wild genotype of MDR1 C3435T and its mutant types. In conclusion, the pharmacokinetics of MDRI C3435T.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Hidrocarburo de Aril Hidroxilasas/genética , Lansoprazol/farmacocinética , Polimorfismo Genético , Subfamilia B de Transportador de Casetes de Unión a ATP , Administración Oral , Adulto , Citocromo P-450 CYP2C19 , Humanos , Lansoprazol/administración & dosificaciónRESUMEN
In this study, we aimed to investigate the quality characteristics, antioxidant activity, and sensory traits of meringue Jeung-pyun with different amounts of cacao bean husk powder. Based on our analyses, high cacao bean husk content resulted in an increase in certain Jeung-pyun qualities, such as the L values, b values, hardness, gumminess, and number of pores, whereas the moisture content, pH, pore size, adhesiveness, cohesiveness, and chewiness significantly decreased. Electronic tongue analysis showed that the intensity of sourness, saltiness, and umami increased with the amount of cacao bean husk added. For the sensory characteristics, C6 demonstrated the highest ranking for all test items. Furthermore, it was found that the addition of cacao bean husks increased the antioxidant activity of the Jeung-pyun (p < 0.001). Therefore, these results suggest that Jeung-pyun produced with a mixing ratio of C6 has excellent qualities, antioxidant activities, and sensory characteristics.
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OBJECTIVE: It is very important to develop a new therapeutic strategy to cope with the increasing morbidity and mortality of chronic kidney disease (CKD). As a kind of physical therapy, low intensity pulsed ultrasound (LIPUS) has remarkable anti-inflammatory and repair-promoting effects and is expected to become a new therapeutic method for CKD. This study aims to clarify the treatment effect of LIPUS on CKD-related renal inflammation and fibrosis, and to further explore the potential signal network of LIPUS treatment for ameliorating chronic renal injury. METHODS: A rat model simulating the progress of CKD was established by twice tail-vein injection of Adriamycin (ADR). Under anesthesia, bilateral kidneys of CKD rats were continuously stimulated by LIPUS for four weeks. The parameters of LIPUS were 1.0 MHz, 60 mW/cm2, 50% duty cycle and 20 min/d. RESULTS: LIPUS treatment effectively inhibited ADR-induced renal inflammation and fibrosis, and improved CKD-related to oxidative stress and ferroptosis. In addition, the therapeutic effect of LIPUS is closely related to the regulation of TGF-ß1/Smad and Nrf2/keap1/HO-1 signalling pathways. DISCUSSION: This study provides a new direction for further mechanism research and lays an important foundation for clinical trials.
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Ferroptosis , Insuficiencia Renal Crónica , Animales , Ratas , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Riñón , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/terapia , Doxorrubicina/toxicidad , InflamaciónRESUMEN
Cholesterol regulates the signaling of µ-opioid receptor in cell models, but it has not been demonstrated in mice or humans. Whether cholesterol regulates the signaling by mechanisms other than supporting the entirety of lipid raft microdomains is still unknown. By modulating cholesterol-enriched lipid raft microdomains and/or total cellular cholesterol contents in human embryonic kidney cells stably expressing µ-opioid receptor, we concluded that cholesterol stabilized opioid signaling both by supporting the lipid raft's entirety and by facilitating G protein coupling. Similar phenomena were observed in the primary rat hippocampal neurons. In addition, reducing the brain cholesterol level with simvastatin impaired the analgesic effect of opioids in mice, whereas the opioid analgesic effect was enhanced in mice fed a high-cholesterol diet. Furthermore, when the records of patients were analyzed, an inverse correlation between cholesterol levels and fentanyl doses used for anesthesia was identified, which suggested the mechanisms above could also be applicable to humans. Our results identified the interaction between opioids and cholesterol, which should be considered in clinics as a probable route for drug-drug interaction. Our studies also suggested that a low cholesterol level could lead to clinical issues, such as the observed impairment in opioid functions.
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Analgesia , Analgésicos Opioides/metabolismo , Colesterol/metabolismo , Transducción de Señal , Analgésicos Opioides/farmacología , Animales , Colesterol en la Dieta/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Fentanilo/farmacología , Células HEK293 , Humanos , Masculino , Microdominios de Membrana/efectos de los fármacos , Ratones , Morfolinas/farmacología , Neuronas/citología , Ratas , Receptores Opioides mu/metabolismo , Transducción de Señal/efectos de los fármacos , Simvastatina/farmacologíaRESUMEN
A new role of G protein-coupled receptor (GPCR) phosphorylation was demonstrated in the current studies by using the µ-opioid receptor (OPRM1) as a model. Morphine induces a low level of receptor phosphorylation and uses the PKCε pathway to induce ERK phosphorylation and receptor desensitization, whereas etorphine, fentanyl, and [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) induce extensive receptor phosphorylation and use the ß-arrestin2 pathway. Blocking OPRM1 phosphorylation (by mutating Ser363, Thr370 and Ser375 to Ala) enabled etorphine, fentanyl, and DAMGO to use the PKCε pathway. This was not due to the decreased recruitment of ß-arrestin2 to the receptor signaling complex, because these agonists were unable to use the PKCε pathway when ß-arrestin2 was absent. In addition, overexpressing G protein-coupled receptor kinase 2 (GRK2) decreased the ability of morphine to activate PKCε, whereas overexpressing dominant-negative GRK2 enabled etorphine, fentanyl, and DAMGO to activate PKCε. Furthermore, by overexpressing wild-type OPRM1 and a phosphorylation-deficient mutant in primary cultures of hippocampal neurons, we demonstrated that receptor phosphorylation contributes to the differential effects of agonists on dendritic spine stability. Phosphorylation blockage made etorphine, fentanyl, and DAMGO function as morphine in the primary cultures. Therefore, agonist-dependent phosphorylation of GPCR regulates the activation of the PKC pathway and the subsequent responses.
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Espinas Dendríticas/metabolismo , Proteína Quinasa C-epsilon/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos Opioides/farmacología , Animales , Arrestinas/metabolismo , Línea Celular , Espinas Dendríticas/efectos de los fármacos , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Etorfina/farmacología , Fentanilo/farmacología , Humanos , Ratones , Morfina/farmacología , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , beta-ArrestinasRESUMEN
BACKGROUND: A cholesterol-palmitoyl interaction has been reported to occur in the dimeric interface of the ß2-adrenergic receptor crystal structure. We sought to investigate whether a similar phenomenon could be observed with µ-opioid receptor (OPRM1), and if so, to assess the role of cholesterol in this class of G protein-coupled receptor (GPCR) signaling. RESULTS: C3.55(170) was determined to be the palmitoylation site of OPRM1. Mutation of this Cys to Ala did not affect the binding of agonists, but attenuated receptor signaling and decreased cholesterol associated with the receptor signaling complex. In addition, both attenuation of receptor palmitoylation (by mutation of C3.55[170] to Ala) and inhibition of cholesterol synthesis (by treating the cells with simvastatin, a HMG-CoA reductase inhibitor) impaired receptor signaling, possibly by decreasing receptor homodimerization and Gαi2 coupling; this was demonstrated by co-immunoprecipitation, immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) analyses. A computational model of the OPRM1 homodimer structure indicated that a specific cholesterol-palmitoyl interaction can facilitate OPRM1 homodimerization at the TMH4-TMH4 interface. CONCLUSIONS: We demonstrate that C3.55(170) is the palmitoylation site of OPRM1 and identify a cholesterol-palmitoyl interaction in the OPRM1 complex. Our findings suggest that this interaction contributes to OPRM1 signaling by facilitating receptor homodimerization and G protein coupling. This conclusion is supported by computational modeling of the OPRM1 homodimer.
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Colesterol/metabolismo , Subunidad alfa de la Proteína de Unión al GTP Gi2/metabolismo , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Cisteína/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismo , Lipoilación/fisiología , Fosforilación/fisiología , Multimerización de Proteína/fisiología , Receptores Opioides mu/genética , Transducción de Señal/fisiologíaRESUMEN
RATIONALE: Prenylated flavonoids and isoflavonoids are widely distributed throughout the plant kingdom, with many biological effects. Psoralea corylifolia, which contains many kinds of prenylated components, has been widely used as a medicinal plant in Asia and India for thousands of years. The goal of this study was to characterize the components in P. corylifolia using a liquid chromatography with diode-array detection and quadrupole time-of-flight mass spectrometry (LC-DAD/Q-TOF-MS) method, and to elucidate the fragmentation behavior of the different prenyl substituent groups and their appropriate characteristic pathways in positive ion mode. METHODS: The calculated accurate masses of the protonated molecules, the fragment ions, the retention behavior, and the data from UV spectra were used for identification of the components in P. corylifolia. RESULTS: A total of 45 compounds, including 43 prenylated components, were identified or tentatively identified in P. corylifolia. Different diagnostic fragment ions and neutral losses were observed in different prenyl substructures: neutral loss of 56 Da (C(4)H(8)) and a fragment ion at m/z 69 (C(5)H(9)(+)) were generated by a prenyl chain; neutral losses of 42 Da (C(3)H(6)), 54 Da (C(4)H(6)), 15 Da (CH(3â¢)) and 16 Da (CH(4)) were observed in a ring-closed prenyl group; neutral losses of 72 Da (C(4)H(8)O), 60 Da (C(2)H(4)O(2)), 58 Da (C(3)H(6)O) and 18 Da (H(2)O) were detected in a 2,2-dimethyl-3,4-dihydroxydihydropyran ring; neutral losses of 72 Da (C(4)H(8)O), 60 Da (C(3)H(8)O) and 18 Da (H(2)O) were yielded from a 2,2-dimethyl-3-hydroxydihydropyran ring, a 2-(1-hydroxy-1-methylethyl)dihydrofuran ring or a 1-hydroxy-3-methylbut-3-enyl chain. CONCLUSIONS: This method can be applied for analysis of prenylated components in P. corylifolia and other herbal medicines.
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Cromatografía Liquida/métodos , Flavonoides/química , Espectrometría de Masas/métodos , Psoralea/química , Flavonoides/análisis , Flavonoides/clasificación , Frutas/química , Modelos Moleculares , Extractos Vegetales/química , PrenilaciónRESUMEN
The objective of the study is to investigate the brain development and atrophy of Diannan small-ear pigs in different ages using magnetic resonance imaging (MRI). A total of 12 Diannan small-ear pigs were included and divided into the young group, adult group, and middle-and-old age (M&O) group according to their age. The brain structure of pigs was scanned using MRI, and the brain data obtained were statistically analyzed by signal conversion and image reconstruction. Compared with the young group, the signals of most brain structures in the adult group and M&O group were significantly decreased (p < 0.05). Compared with the adult group, the signal intensity of the right caudate nucleus and the right lateral ventricle in the M&O group was significantly increased, while the signal intensity of other regions was almost significantly decreased (p < 0.05). Compared with the young group, both adult and M&O groups had some degree of brain atrophy. Brain atrophy in the precuneus and the inferior temporal gyrus was more predominant in the M&O group in comparison with the adult group. The present study demonstrated that the brain signal of Diannan small-ear pigs gradually diminished with age, while the degree of brain atrophy was the opposite, providing the basic data on the brain of Diannan small-ear pigs.
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The cellular level of neurogenic differentiation 1 (NeuroD) is modulated differentially by mu-opioid receptor agonists; fentanyl increases NeuroD level by reducing the amount of microRNA-190 (miR-190), an inhibitor of NeuroD expression, whereas morphine does not alter NeuroD level. In the current study, NeuroD activity was demonstrated to be also under agonist-dependent regulation. After 3 d of treatment, morphine and fentanyl decreased the activity of the Ca(2+)/calmodulin-dependent protein kinase II alpha (CaMKIIalpha), which phosphorylates and activates NeuroD. Because NeuroD activity is determined by both the CaMKIIalpha activity and the cellular NeuroD level, the overall NeuroD activity was reduced by morphine, but maintained during fentanyl treatment. The differential effects of agonists on NeuroD activity were further confirmed by measuring the mRNA levels of four NeuroD downstream targets: doublecortin, Notch1, neurogenic differentiation 4, and Roundabout 1. Decreased dendritic spine stability and mu-opioid receptor signaling capability were also observed when NeuroD activity was attenuated by miR-190 overexpression or treatment with KN93, a CaMKIIalpha inhibitor. The decrease could be rescued by NeuroD overexpression, which restored NeuroD activity to the basal level. Furthermore, elevating NeuroD activity attenuated the morphine-induced decrease in dendritic spine stability. Therefore, by regulating NeuroD activity, mu-opioid receptor agonists modulate the stability of dendritic spines.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Espinas Dendríticas/efectos de los fármacos , Fentanilo/farmacología , Morfina/farmacología , Narcóticos/farmacología , Neuronas , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Bencilaminas/farmacología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Células Cultivadas , Espinas Dendríticas/fisiología , Relación Dosis-Respuesta a Droga , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Fluorescentes Verdes/genética , Hipocampo/citología , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/ultraestructura , Neuropéptidos/genética , Neuropéptidos/metabolismo , Fosforilación/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Receptores Opioides mu/metabolismo , Sulfonamidas/farmacología , Factores de Tiempo , Transducción Genética/métodos , Proteínas RoundaboutRESUMEN
Mu-opioid receptor regulates microRNA-190 (miR-190) in an agonist-dependent manner; fentanyl, but not morphine, decreases the miR-190 level in rat primary hippocampal neuron cultures and in mouse hippocampi. In this study, the correlation between the cellular content of miR-190 and the mRNA level of its host gene, talin2, suggested that fentanyl decreases the miR-190 level by inhibiting the transcription of talin2. Fentanyl-induced beta-arrestin2-mediated ERK phosphorylation led to the phosphorylation of Yin Yang 1 (YY1). In addition, YY1 phosphorylation impaired the association of YY1 with the -208 to -200 region on the Talin2 promoter, and this association was essential for YY1 to stimulate the transcription of talin2. Thus, fentanyl decreased the transcription of talin2 and subsequently the cellular level of miR-190 by inducing YY1 phosphorylation. In contrast, because morphine induces ERK phosphorylation via the protein kinase C pathway, morphine did not induce YY1 phosphorylation and had no effect on the transcription of talin2 and the cellular content of miR-190. This study therefore delineates a signaling pathway that mediates the effects of fentanyl on miR-190 expression.