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1.
Adv Exp Med Biol ; 1131: 965-984, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646541

RESUMO

Synaptic plasticity is a fundamental property of neurons referring to the activity-dependent changes in the strength and efficacy of synaptic transmission at preexisting synapses. Such changes can last from milliseconds to hours, days, or even longer and are involved in learning and memory as well as in development and response of the brain to injuries. Several types of synaptic plasticity have been described across neuronal types, brain regions, and species, but all of them share in one way or another capital importance of Ca2+-mediated processes. In this chapter, we will focus on the Ca2+-dependent events necessary for the induction and expression of multiple forms of synaptic plasticity.


Assuntos
Cálcio , Plasticidade Neuronal , Sinapses , Cálcio/metabolismo , Humanos , Potenciação de Longa Duração , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Transmissão Sináptica
2.
Life Sci ; 233: 116729, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31386876

RESUMO

AIMS: Glutamatergic receptors are important targets of ethanol. Intake of ethanol may produce analgesic effects. The present study examined the effects of ethanol on the activity of ionotropic glutamate receptors in spinal cord substantia gelatinosa (SG) neurons, critical neurons involved in nociceptive transmission. MAIN METHODS: Whole-cell recordings were made from SG neurons of the lumbar spinal cord slices from 15 to 20-day-old rats. Ethanol and glutamate receptor agonists or antagonists were applied by superfusion. KEY FINDING: Ethanol (50 and 100 mM) applied by superfusion for 5 min dose-dependently decreased the amplitude of evoked excitatory postsynaptic potential in SG neurons. Superfusion of ethanol (100 mM) for 15 min consistently inhibited NMDA- or AMPA-induced depolarizations in SG neurons. Ethanol (100 mM) also inhibited the depolarizations induced by glutamate. However, ethanol inhibition of glutamate-induced responses significantly decreased at 10-15 min following continuous superfusion, suggesting the development of acute tolerance to the inhibition during prolonged exposure. Application of MPEP hydrochloride (an antagonist of metabotropic glutamate receptor [mGluR] 5) or GF109203X (a protein kinase C [PKC] inhibitor), together with ethanol significantly blocked the tolerance. The inhibition by ethanol of the NMDA-induced, but not AMPA-induced, depolarizations significantly decreased at 15 min during continuous superfusion while ACPD (a mGluR agonist) was co-applied with ethanol. SIGNIFICANCE: The results suggest that (1) ethanol exposure may inhibit ionotropic glutamate receptor-mediated neurotransmission; (2) regulation of NMDA receptor function by mGluR5/PKC pathways may be involved in the development of the tolerance to ethanol inhibition of glutamate-induced responses during prolonged exposure in SG neurons.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Neurônios/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores Ionotrópicos de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Substância Gelatinosa/metabolismo , Animais , Agonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores , Potenciais da Membrana , Neurônios/citologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Substância Gelatinosa/citologia , Substância Gelatinosa/efeitos dos fármacos , Transmissão Sináptica
3.
Sheng Li Xue Bao ; 71(4): 547-554, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31440751

RESUMO

The aim of the present study was to reveal the role of cortical-striatum postsynaptic dopamine D2 receptor (D2R) in improving motor behavioral dysfunction in Parkinson's disease (PD) mice by exercise. C57/BL6 male adult mice were randomly divided into control, PD and PD plus exercise groups. The mice were injected with 6-OHDA in striatum to establish a unilateral injury PD model. The exercise intervention program was uniform speed running (16 m/min, 40 min/d, 5 d per week for 4 weeks). Autonomic activity of mice was tested by open field test. Cortical-striatum synaptic transmission efficiency was assessed by peak amplitude of field excitatory postsynaptic potential (fEPSP) recorded from in vitro brain slides. Meanwhile, the effects of D2R agonist on autonomic activity and cortical-striatal synaptic transmission were observed. The results showed that, compared with PD group, PD plus exercise group exhibited significantly increased autonomic motor distance and proportion of fast-moving (P < 0.05), as well as decreased maximum amplitude of fEPSP under increasing stimulation intensity (0.75-3.00 pA) (P < 0.05) and slope of stimulus-response curve. Compared with PD mice without D2R agonist, the movement distance and rapid movement ratio of PD mice treated with D2R agonist were increased significantly (P < 0.05), whereas fEPSP peak amplitude (P < 0.05) and the slope of stimulus-response curve were decreased. These results indicate that either early exercise intervention or D2R agonist treatment can inhibit the abnormal increase of cortical-striatum synaptic transmission and improve the autonomic motor ability in PD mice, suggesting that the cortical-striatum synaptic D2R may be an important molecular target for exercise to improve the autonomic motor ability of PD mice.


Assuntos
Corpo Estriado/fisiologia , Doença de Parkinson/terapia , Condicionamento Físico Animal , Receptores de Dopamina D2/fisiologia , Transmissão Sináptica , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxidopamina , Doença de Parkinson/fisiopatologia , Distribuição Aleatória , Receptores de Dopamina D2/agonistas
4.
Neuron ; 103(3): 380-394, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394063

RESUMO

The Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) was touted as a memory molecule, even before its involvement in long-term potentiation (LTP) was shown. The enzyme has not disappointed, with subsequent demonstrations of remarkable structural and regulatory properties. Its neuronal functions now extend to long-term depression (LTD), and last year saw the first direct evidence for memory storage by CaMKII. Although CaMKII may have taken the spotlight, it is a member of a large family of diverse and interesting CaM kinases. Our aim is to place CaMKII in context of the other CaM kinases and then review certain aspects of this kinase that are of current interest.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Sequência de Aminoácidos , Animais , Encéfalo/enzimologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Cognição/fisiologia , Humanos , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Modelos Moleculares , Família Multigênica , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/fisiologia , Fosforilação , Conformação Proteica , Domínios Proteicos , Mapeamento de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/classificação , Proteínas Serina-Treonina Quinases/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica
5.
Nat Commun ; 10(1): 2937, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270315

RESUMO

During the generation of rhythmic movements, most spinal neurons receive an oscillatory synaptic drive. The neuronal architecture underlying this drive is unknown, and the corresponding network size and sparseness have not yet been addressed. If the input originates from a small central pattern generator (CPG) with dense divergent connectivity, it will induce correlated input to all receiving neurons, while sparse convergent wiring will induce a weak correlation, if any. Here, we use pairwise recordings of spinal neurons to measure synaptic correlations and thus infer the wiring architecture qualitatively. A strong correlation on a slow timescale implies functional relatedness and a common source, which will also cause correlation on fast timescale due to shared synaptic connections. However, we consistently find marginal coupling between slow and fast correlations regardless of neuronal identity. This suggests either sparse convergent connectivity or a CPG network with recurrent inhibition that actively decorrelates common input.


Assuntos
Medula Espinal/fisiologia , Animais , Feminino , Cinética , Masculino , Modelos Neurológicos , Neurônios/química , Neurônios/fisiologia , Medula Espinal/química , Sinapses/fisiologia , Transmissão Sináptica , Fatores de Tempo , Tartarugas
6.
Neuron ; 103(4): 617-626.e6, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31257103

RESUMO

The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human embryonic stem cell-derived neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change-of-function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting that human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.


Assuntos
Moléculas de Adesão Celular Neuronais/fisiologia , Transmissão Sináptica/fisiologia , Animais , Transtorno Autístico/genética , Moléculas de Adesão Celular Neuronais/genética , Células Cultivadas , Córtex Cerebral/fisiologia , Células-Tronco Embrionárias/citologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Genes Reporter , Ácido Glutâmico/fisiologia , Humanos , Camundongos , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Mutação de Sentido Incorreto , Neurogênese , Neurônios/fisiologia , Fenótipo , Receptores de Glutamato/fisiologia , Especificidade da Espécie , Sinapses/química
7.
Br J Anaesth ; 123(3): 335-349, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31303268

RESUMO

Systemic administration of the local anaesthetic lidocaine is antinociceptive in both acute and chronic pain states, especially in acute postoperative and chronic neuropathic pain. These effects cannot be explained by its voltage-gated sodium channel blocking properties alone, but the responsible mechanisms are still elusive. This narrative review focuses on available experimental evidence of the molecular mechanisms by which systemic lidocaine exerts its clinically documented analgesic effects. These include effects on the peripheral nervous system and CNS, where lidocaine acts via silencing ectopic discharges, suppression of inflammatory processes, and modulation of inhibitory and excitatory neurotransmission. We highlight promising objectives for future research to further unravel these antinociceptive mechanisms, which subsequently may facilitate the development of new analgesic strategies and therapies for acute and chronic pain.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos/farmacologia , Anestésicos Locais/farmacologia , Dor Crônica/tratamento farmacológico , Lidocaína/farmacologia , Terapia de Alvo Molecular/métodos , Dor Aguda/metabolismo , Analgésicos/uso terapêutico , Anestésicos Locais/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Dor Crônica/metabolismo , Humanos , Canais Iônicos/efeitos dos fármacos , Lidocaína/uso terapêutico , Transmissão Sináptica/efeitos dos fármacos
8.
Neuron ; 103(4): 719-733.e7, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31253469

RESUMO

A central goal in learning and memory research is to reveal the neural substrates underlying episodic memory formation. The hallmark of sequential spatial trajectory learning, a model of episodic memory, has remained equivocal, with proposals ranging from de novo creation of compressed sequential replay from blank slate networks to selection of pre-existing compressed preplay sequences. Here, we show that increased millisecond-timescale activation of cell assemblies expressed during de novo sequential experience and increased neuronal firing rate correlations can explain the difference between post-experience trajectory replay and robust preplay. This increased activation results from an improved neuronal tuning to specific cell assemblies, higher recruitment of experience-tuned neurons into pre-existing cell assemblies, and increased recruitment of cell assemblies in replay. In contrast, changes in overall neuronal and cell assembly temporal order within extended sequences do not account for sequential trajectory learning. We propose the coordinated strengthening of cell assemblies played sequentially on robust pre-existing temporal frameworks could support rapid formation of episodic-like memory.


Assuntos
Região CA1 Hipocampal/fisiologia , Memória Episódica , Modelos Neurológicos , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Memória Espacial , Animais , Região CA1 Hipocampal/citologia , Simulação por Computador , Locomoção/fisiologia , Masculino , Ratos , Ratos Long-Evans , Sono/fisiologia , Distribuições Estatísticas , Transmissão Sináptica/fisiologia , Fatores de Tempo
9.
Nat Commun ; 10(1): 2746, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227712

RESUMO

Nicotinic acetylcholine receptors (nAChRs) mediate and modulate synaptic transmission throughout the brain, and contribute to learning, memory, and behavior. Dysregulation of α7-type nAChRs in neuropsychiatric as well as immunological and oncological diseases makes them attractive targets for pharmaceutical development. Recently, we identified NACHO as an essential chaperone for α7 nAChRs. Leveraging the robust recombinant expression of α7 nAChRs with NACHO, we utilized genome-wide cDNA library screening and discovered that several anti-apoptotic Bcl-2 family proteins further upregulate receptor assembly and cell surface expression. These effects are mediated by an intracellular motif on α7 that resembles the BH3 binding domain of pro-apoptotic Bcl-2 proteins, and can be blocked by BH3 mimetic Bcl-2 inhibitors. Overexpression of Bcl-2 member Mcl-1 in neurons enhanced surface expression of endogenous α7 nAChRs, while a combination of chemotherapeutic Bcl2-inhibitors suppressed neuronal α7 receptor assembly. These results demonstrate that Bcl-2 proteins link α7 nAChR assembly to cell survival pathways.


Assuntos
Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neurônios/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Motivos de Aminoácidos/genética , Animais , Benzotiazóis/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células HEK293 , Humanos , Isoquinolinas/farmacologia , Chaperonas Moleculares/metabolismo , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Cultura Primária de Células , Ligação Proteica/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinas/farmacologia , Ratos , Transmissão Sináptica/efeitos dos fármacos , Tiofenos/farmacologia , Regulação para Cima , Receptor Nicotínico de Acetilcolina alfa7/genética
10.
Nat Commun ; 10(1): 2676, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213599

RESUMO

Wearable and skin electronics benefit from mechanically soft and stretchable materials to conform to curved and dynamic surfaces, thereby enabling seamless integration with the human body. However, such materials are challenging to process using traditional microelectronics techniques. Here, stretchable transistor arrays are patterned exclusively from solution by inkjet printing of polymers and carbon nanotubes. The additive, non-contact and maskless nature of inkjet printing provides a simple, inexpensive and scalable route for stacking and patterning these chemically-sensitive materials over large areas. The transistors, which are stable at ambient conditions, display mobilities as high as 30 cm2 V-1 s-1 and currents per channel width of 0.2 mA cm-1 at operation voltages as low as 1 V, owing to the ionic character of their printed gate dielectric. Furthermore, these transistors with double-layer capacitive dielectric can mimic the synaptic behavior of neurons, making them interesting for conformal brain-machine interfaces and other wearable bioelectronics.


Assuntos
Eletrônica Médica/métodos , Nanotecnologia/métodos , Impressão/métodos , Dispositivos Eletrônicos Vestíveis , Interfaces Cérebro-Computador , Desenho de Equipamento , Humanos , Nanotubos de Carbono/química , Neurônios/fisiologia , Polímeros/química , Transmissão Sináptica/fisiologia , Transistores Eletrônicos
11.
Yakugaku Zasshi ; 139(6): 847-852, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31155524

RESUMO

Neurons differentiated from neural stem cells mature to form a neuronal network. Neuronal maturation enables neurotransmission that regulates brain function. Therefore, abnormal neuronal differentiation causes dysfunction in neurotransmission, and is involved in the onset of various neuropsychiatric disorders. Most of the drugs currently available for the treatment of neuropsychiatric disorders act on membrane receptors and reuptake transporters of neurotransmitters, and control neurotransmission. These membrane proteins have a high affinity for a specific neurotransmitter, and are highly expressed in synapses. By contrast, xenobiotic transporters have a relatively lower affinity for neurotransmitters, but widely recognize various organic compounds, and are also expressed in brain neural cells. It has remained largely unknown why such xenobiotic transporters are expressed in neural cells that play a key role in neurotransmission. We have therefore attempted to clarify the physiological roles of organic cation transporters (OCTs) in neural stem cells in order to obtain new insight into the treatment of neuropsychiatric disorders. The carnitine/organic cation transporter OCTN1/SLC22A4 is expressed at much higher levels in neural stem cells compared with other OCTs, and promotes their differentiation into neurons through the uptake of the food-derived hydrophilic antioxidant ergothioneine after oral administration. In this review, we introduce current topics on the physiological/pathophysiological roles of OCTs in neural stem cells, and discuss their possible application to the treatment of neuropsychiatric disorders.


Assuntos
Diferenciação Celular/genética , Transtornos Mentais/etiologia , Transtornos Mentais/terapia , Terapia de Alvo Molecular , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/terapia , Neurônios/fisiologia , Proteínas de Transporte de Cátions Orgânicos/fisiologia , Animais , Antioxidantes/metabolismo , Ergotioneína/metabolismo , Humanos , Camundongos , Células-Tronco Neurais/fisiologia , Neurotransmissores/fisiologia , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transmissão Sináptica
12.
Nat Commun ; 10(1): 2413, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160571

RESUMO

Synapotagmin-1 (Syt1) interacts with both SNARE proteins and lipid membranes to synchronize neurotransmitter release to calcium (Ca2+) influx. Here we report the cryo-electron microscopy structure of the Syt1-SNARE complex on anionic-lipid containing membranes. Under resting conditions, the Syt1 C2 domains bind the membrane with a magnesium (Mg2+)-mediated partial insertion of the aliphatic loops, alongside weak interactions with the anionic lipid headgroups. The C2B domain concurrently interacts the SNARE bundle via the 'primary' interface and is positioned between the SNAREpins and the membrane. In this configuration, Syt1 is projected to sterically delay the complete assembly of the associated SNAREpins and thus, contribute to clamping fusion. This Syt1-SNARE organization is disrupted upon Ca2+-influx as Syt1 reorients into the membrane, likely displacing the attached SNAREpins and reversing the fusion clamp. We thus conclude that the cation (Mg2+/Ca2+) dependent membrane interaction is a key determinant of the dual clamp/activator function of Synaptotagmin-1.


Assuntos
Membrana Celular/ultraestrutura , Lipídeos de Membrana/metabolismo , Proteínas SNARE/ultraestrutura , Sinaptotagmina I/ultraestrutura , Animais , Cálcio/metabolismo , Membrana Celular/metabolismo , Microscopia Crioeletrônica , Magnésio/metabolismo , Fusão de Membrana , Neurotransmissores/metabolismo , Ligação Proteica , Ratos , Proteínas SNARE/metabolismo , Transmissão Sináptica , Sinaptotagmina I/metabolismo
13.
Nat Neurosci ; 22(7): 1053-1056, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209376

RESUMO

The lateral habenula encodes aversive stimuli contributing to negative emotional states during drug withdrawal. Here we report that morphine withdrawal in mice leads to microglia adaptations and diminishes glutamatergic transmission onto raphe-projecting lateral habenula neurons. Chemogenetic inhibition of this circuit promotes morphine withdrawal-like social deficits. Morphine withdrawal-driven synaptic plasticity and reduced sociability require tumor necrosis factor-α (TNF-α) release and neuronal TNF receptor 1 activation. Hence, habenular cytokines control synaptic and behavioral adaptations during drug withdrawal.


Assuntos
Citocinas/fisiologia , Habenula/fisiologia , Morfina/efeitos adversos , Comportamento Social , Síndrome de Abstinência a Substâncias/fisiopatologia , Transmissão Sináptica/fisiologia , Adaptação Psicológica , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/fisiologia , Naloxona/toxicidade , Plasticidade Neuronal , Distribuição Aleatória , Receptores de Glutamato/análise , Receptores de N-Metil-D-Aspartato/análise , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Síndrome de Abstinência a Substâncias/psicologia , Fator de Necrose Tumoral alfa/fisiologia
14.
BMC Complement Altern Med ; 19(1): 128, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196061

RESUMO

BACKGROUND: Salvia officinalis has been used successfully for the treatment of hot flushes and excessive sweating during menopause. However, modes of actions have not been elucidated conclusively. We explored its pharmacology beyond any hormonal activity with a focus on neurologic impulse transmission. METHODS: A hydroalcoholic, thujone-free extract from freshly harvested Salvia officinalis leaves (A.Vogel Menosan®) was investigated in an acetylcholinesterase enzyme assay and several receptor binding assays (adrenergic alpha 2A, GABA (benzodiazepine site), GABAB; muscarinic M3, µ-opioid, serotonin 5-HT1A, serotonin 5-HT2B, serotonin 5-HT2C and serotonin transporter). The influence of the manufacturing process on additional extracts from different fresh or dry plant parts was studied. RESULTS: The Salvia officinalis extract replaced 50% of specific ligand binding to GABAA and GABAB receptors at an inhibitory concentration (IC50) of 89 and 229 µg/ml, respectively. Strong binding affinity was observed for the adrenergic α2A receptor, µ-opioid receptors, muscarinic M3 receptors, and serotonin 5-HT1A receptors, with IC50 values of 15 µg/ml, 20 µg/ml, 25 µg/ml and 19 µg/ml, respectively. Moderate interference with 5-HT2B, 5-HT2C receptors, and the human serotonin transporter was found, all with IC50 values above 32 µg/ml. Receptor binding data of Salvia extract were confirmed in native female hypothalamic tissue from two women (51 and 37 years old). Use of freshly harvested Salvia leaves resulted in 2- to 4-fold higher activity/lower IC50 values compared to extracts from dried plants or stipes. CONCLUSION: Our results suggest potent modulation of neuro-receptors and of serotonin transporters as mode of action for Salvia officinalis alcoholic extract, which may normalize thermoregulation and possibly also mental impairment during menopause.


Assuntos
Fogachos/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Salvia officinalis , Transmissão Sináptica/efeitos dos fármacos , Adulto , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Extratos Vegetais/farmacologia
15.
Life Sci ; 231: 116567, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202839

RESUMO

AIMS: Metabotropic glutamate receptor 5 (mGluR5), a member of group I mGluR, exerts its effect via elevation of intracellular Ca2+ level. We here characterized Ca2+ signals in the tsA201 cells transfected with mGluR5 and investigated the role of passages for mGluR5-induced Ca2+ signals in synaptic plasticity. MAIN METHODS: Using a genetically encoded Ca2+ indicator, GCamp2, Ca2+ signals were reliably induced by bath application of (S)-3,5-dihydroxyphenylglycine, the group I mGluR agonist, in the tsA201 cells transfected with mGluR5. Using whole-cell recordings in the substantia gelatinosa (SG) neurons of the spinal trigeminal subnucleus caudalis (Vc), excitatory postsynaptic currents were recorded by stimulating the trigeminal tract. KEY FINDINGS: Ca2+ signals were mediated by "classical" or "canonical" transient receptor potential (TRPC) channels, particularly TRPC1/3/4/6, but not TRPC5, naturally existing in the tsA201 cells. Interestingly, the induction of Ca2+ signals was independent of the phospholipase C signaling pathway; instead, it critically involves the cyclic adenosine diphosphate ribose/ryanodine receptor-dependent signaling pathway and only partially protein kinase C. On the other hand, both TRPC3 and TRPC4 mediated mGluR1/5-induced long-lasting potentiation of excitatory synaptic transmission from the trigeminal primary afferents to the SG neurons of the Vc. SIGNIFICANCE: This study demonstrates that endogenous TRPC channels contribute to mGluR5-induced Ca2+ signals in tsA201 cells and synaptic plasticity at excitatory synapses.


Assuntos
Sinalização do Cálcio/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Receptor de Glutamato Metabotrópico 5/metabolismo , Canais de Cátion TRPC/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores , Feminino , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Sinapses/metabolismo , Transmissão Sináptica , Nervo Trigêmeo/metabolismo , Núcleo Espinal do Trigêmeo/metabolismo
16.
Mar Drugs ; 17(5)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137661

RESUMO

Pinnatoxins (PnTXs) A-H constitute an emerging family belonging to the cyclic imine group of phycotoxins. Interest has been focused on these fast-acting and highly-potent toxins because they are widely found in contaminated shellfish. Despite their highly complex molecular structure, PnTXs have been chemically synthetized and demonstrated to act on various nicotinic acetylcholine receptor (nAChR) subtypes. In the present work, PnTX-A, PnTX-G and analogue, obtained by chemical synthesis with a high degree of purity (>98%), have been studied in vivo and in vitro on adult mouse and isolated nerve-muscle preparations expressing the mature muscle-type (α1)2ß1δε nAChR. The results show that PnTX-A and G acted on the neuromuscular system of anesthetized mice and blocked the compound muscle action potential (CMAP) in a dose- and time-dependent manner, using a minimally invasive electrophysiological method. The CMAP block produced by both toxins in vivo was reversible within 6-8 h. PnTX-A and G, applied to isolated extensor digitorum longus nerve-muscle preparations, blocked reversibly isometric twitches evoked by nerve stimulation. The action of PnTX-A was reversed by 3,4-diaminopyridine. Both toxins exerted no direct action on muscle fibers, as revealed by direct muscle stimulation. PnTX-A and G blocked synaptic transmission at mouse neuromuscular junctions and PnTX-A amino ketone analogue (containing an open form of the imine ring) had no effect on neuromuscular transmission. These results indicate the importance of the cyclic imine for interacting with the adult mammalian muscle-type nAChR. Modeling and docking studies revealed molecular determinants responsible for the interaction of PnTXs with the muscle-type nAChR.


Assuntos
Alcaloides/farmacologia , Músculo Esquelético/efeitos dos fármacos , Compostos de Espiro/farmacologia , Esteróis/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Alcaloides/síntese química , Animais , Feminino , Masculino , Camundongos , Bloqueadores Neuromusculares/síntese química , Bloqueadores Neuromusculares/farmacologia , Antagonistas Nicotínicos/síntese química , Antagonistas Nicotínicos/farmacologia , Ligação Proteica/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Compostos de Espiro/síntese química , Esteróis/síntese química
19.
Yakugaku Zasshi ; 139(5): 793-805, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31061349

RESUMO

Angiotensin II (Ang II) is an intrinsic peptide having strong vasopressor effects, and thus, it plays an important role in the physiological regulation of blood pressure. The vasopressor effects of Ang II include direct contraction of myocardium and vascular smooth muscles (SMs) along with aldosterone-mediated sodium retention. In addition, indirect vascular contractions induced by noradrenaline (NA), the release of which is mediated through Ang II receptor type 1 (AT1) existing at the sympathetic nerve terminals (SNTs), also contribute to the vasopressor effects of Ang II. Stimulation of NA release from SNTs by Ang II also occurs in the myocardium leading to an increase in heart rate and cardiac contraction. Furthermore, Ang II enhances the contractions of non-vascular SMs, such as vas deferens, through induction of NA release from the SNTs. We have found that Ang II attenuated vagus nerve stimulation-induced bradycardia in a losartan-sensitive manner. This suggests that Ang II attenuates vagus nerve stimulation-induced bradycardia by inhibiting acetylcholine (ACh) release from the parasympathetic nerve terminals (PNTs) through activation of the AT1 receptor. Ang II was also reported to attenuate the release of ACh from the PNTs in SMs, such as stomach and airway, thus suppressing their contractile functions. There are, however, conflicting reports of the effects of Ang II on parasympathetic nerve-mediated contractile regulation of SMs. In this review, we have highlighted the relevant research articles including our experimental reports on the regulation of sympathetic and parasympathetic nerve-mediated excitation and contraction by Ang II along with the future prospects.


Assuntos
Angiotensina II/fisiologia , Vias Autônomas/fisiologia , Músculo Liso/fisiologia , Contração Miocárdica/genética , Contração Miocárdica/fisiologia , Sistema Nervoso Parassimpático/fisiologia , Sistema Nervoso Simpático/fisiologia , Transmissão Sináptica/genética , Acetilcolina/metabolismo , Angiotensina II/biossíntese , Animais , Frequência Cardíaca/genética , Humanos , Norepinefrina/metabolismo , Ratos , Sistema Nervoso Simpático/metabolismo
20.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075818

RESUMO

Major depressive disorder (MDD) is a debilitating condition, whose high prevalence and multisymptomatic nature set its standing as a leading contributor to global disability. To better understand this psychiatric disease, various pathophysiological mechanisms have been proposed, including changes in monoaminergic neurotransmission, imbalance of excitatory and inhibitory signaling in the brain, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, and abnormalities in normal neurogenesis. While previous findings led to a deeper understanding of the disease, the pathogenesis of MDD has not yet been elucidated. Accumulating evidence has confirmed the association between chronic inflammation and MDD, which is manifested by increased levels of the C-reactive protein, as well as pro-inflammatory cytokines, such as Interleukin 1 beta, Interleukin 6, and the Tumor necrosis factor alpha. Furthermore, recent findings have implicated a related family of cytokines with chemotactic properties, known collectively as chemokines, in many neuroimmune processes relevant to psychiatric disorders. Chemokines are small (8-12 kDa) chemotactic cytokines, which are known to play roles in direct chemotaxis induction, leukocyte and macrophage migration, and inflammatory response propagation. The inflammatory chemokines possess the ability to induce migration of immune cells to the infection site, whereas their homeostatic chemokine counterparts are responsible for recruiting cells for their repair and maintenance. To further support the role of chemokines as central elements to healthy bodily function, recent studies suggest that these proteins demonstrate novel, brain-specific mechanisms including the modulation of neuroendocrine functions, chemotaxis, cell adhesion, and neuroinflammation. Elevated levels of chemokines in patient-derived serum have been detected in individuals diagnosed with major depressive disorder, bipolar disorder, and schizophrenia. Furthermore, despite the considerable heterogeneity of experimental samples and methodologies, existing biomarker studies have clearly demonstrated the important role of chemokines in the pathophysiology of psychiatric disorders. The purpose of this review is to summarize the data from contemporary experimental and clinical studies, and to evaluate available evidence for the role of chemokines in the central nervous system (CNS) under physiological and pathophysiological conditions. In light of recent results, chemokines could be considered as possible peripheral markers of psychiatric disorders, and/or targets for treating depressive disorders.


Assuntos
Quimiocinas/metabolismo , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Humanos , Neurogênese , Plasticidade Neuronal , Receptores de Quimiocinas/metabolismo , Transmissão Sináptica
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