Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Mais filtros

Bases de dados
Tipo de documento
Intervalo de ano de publicação
1.
Nat Chem Biol ; 19(10): 1276-1285, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37550431

RESUMO

Phe-Met-Arg-Phe-amide (FMRFamide)-activated sodium channels (FaNaCs) are a family of channels activated by the neuropeptide FMRFamide, and, to date, the underlying ligand gating mechanism remains unknown. Here we present the high-resolution cryo-electron microscopy structures of Aplysia californica FaNaC in both apo and FMRFamide-bound states. AcFaNaC forms a chalice-shaped trimer and possesses several notable features, including two FaNaC-specific insertion regions, a distinct finger domain and non-domain-swapped transmembrane helix 2 in the transmembrane domain (TMD). One FMRFamide binds to each subunit in a cleft located in the top-most region of the extracellular domain, with participation of residues from the neighboring subunit. Bound FMRFamide adopts an extended conformation. FMRFamide binds tightly to A. californica FaNaC in an N terminus-in manner, which causes collapse of the binding cleft and induces large local conformational rearrangements. Such conformational changes are propagated downward toward the TMD via the palm domain, possibly resulting in outward movement of the TMD and dilation of the ion conduction pore.


Assuntos
Ativação do Canal Iônico , Neuropeptídeos , FMRFamida/metabolismo , FMRFamida/farmacologia , Microscopia Crioeletrônica , Neuropeptídeos/metabolismo , Canais de Sódio/química , Canais de Sódio/metabolismo
2.
Cereb Cortex ; 32(24): 5580-5596, 2022 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-35188969

RESUMO

The excitatory neurons of the medial prefrontal cortex (mPFC) respond to social stimuli. However, little is known about how the neural activity is altered during social avoidance, and whether it could act as a target of low-intensity focused ultrasound stimulation (LIFUS) to rescue social deficits. The present study aimed to investigate the mechanisms of neuronal activities and inflammatory responses underlying the effect of LIFUS on social avoidance. We found that chronic LIFUS stimulation can effectively improve social avoidance in the defeated mice. Calcium imaging recordings by fiber photometry in the defeated mice showed inhibited ensemble activity during social behaviors. LIFUS instantaneously triggered the mPFC neuronal activities, and chronic LIFUS significantly enhanced their neuronal excitation related to social interactions. We further found that the excessive activation of microglial cells and the overexpression of the inflammation signaling, i.e. Toll-like receptors(TLR4)/nuclear factor-kappaB(NF-КB), in mPFC were significantly inhibited by LIFUS. These results suggest that the LIFUS may inhibit social avoidance behavior by reducing activation of the inflammatory response, increasing neuronal excitation, and protecting the integrity of the neuronal structure in the mPFC. Our findings raised the possibility of LIFUS being applied as novel neuromodulation for social avoidance treatment in neuropsychiatric diseases.


Assuntos
Aprendizagem da Esquiva , Derrota Social , Animais , Camundongos , Aprendizagem da Esquiva/fisiologia , Comportamento Social , Estresse Psicológico/psicologia , Córtex Pré-Frontal/fisiologia , Camundongos Endogâmicos C57BL
3.
Proc Natl Acad Sci U S A ; 116(17): 8591-8596, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30967508

RESUMO

Membrane depolarization and intracellular Ca2+ promote activation of the large-conductance Ca2+- and voltage-gated (Slo1) big potassium (BK) channel. We examined the physical interactions that stabilize the closed and open conformations of the ion conduction gate of the human Slo1 channel using electrophysiological and computational approaches. The results show that the closed conformation is stabilized by intersubunit ion-ion interactions involving negative residues (E321 and E324) and positive residues (329RKK331) at the cytoplasmic ends of the transmembrane S6 segments ("RKK ring"). When the channel gate is open, the RKK ring is broken and the positive residues instead make electrostatic interactions with nearby membrane lipid oxygen atoms. E321 and E324 are stabilized by water. When the 329RKK331 residues are mutated to hydrophobic amino acids, these residues form even stronger hydrophobic interactions with the lipid tails to promote the open conformation, shifting the voltage dependence of activation to the negative direction by up to 400 mV and stabilizing the selectivity filter region. Thus, the RKK segment forms electrostatic interactions with oxygen atoms from two sources, other amino acid residues (E321/E324), and membrane lipids, depending on the gate status. Each time the channel opens and closes, the aforementioned interactions are formed and broken. This lipid-dependent Slo1 gating may explain how amphipathic signaling molecules and pharmacologically active agents influence the channel activity, and a similar mechanism may be operative in other ion channels.


Assuntos
Ativação do Canal Iônico/fisiologia , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/química , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Lipídeos de Membrana/química , Lipídeos de Membrana/metabolismo , Cálcio/química , Cálcio/metabolismo , Linhagem Celular , Humanos , Magnésio/química , Magnésio/metabolismo , Simulação de Dinâmica Molecular , Mutação , Potássio/química , Potássio/metabolismo
4.
Sheng Li Xue Bao ; 73(5): 828-834, 2021 Oct 25.
Artigo em Zh | MEDLINE | ID: mdl-34708240

RESUMO

As a kind of mental illness, depression produces great difficulties in clinical diagnosis and treatment, and has a high disability rate. It is urgent to clarify the mechanism of depression to find potential therapeutic targets and effective clinical treatment methods. As a deacetylase, silent mating type information regulator 2 homolog 1 (SIRT1) is involved in many biological processes such as cell aging, cancer, and cardiovascular disease. In recent years, more and more studies have found that SIRT1 gene plays an important role in the pathogenesis of depression, but the mechanism is still unclear. Therefore, this review mainly summarizes the relevant research progress on the role and mechanism of SIRT1 gene in the hippocampus, prefrontal cortex, amygdala, hypothalamic suprachiasmatic nucleus, and nucleus accumbens in depression, in order to provide new ideas for exploring the mechanism and prevention of depression.


Assuntos
Depressão , Sirtuína 1 , Senescência Celular , Depressão/genética , Hipocampo/metabolismo , Humanos , Núcleo Accumbens , Sirtuína 1/genética , Sirtuína 1/metabolismo
5.
Proc Natl Acad Sci U S A ; 113(48): 13905-13910, 2016 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-27849612

RESUMO

Docosahexaenoic acid (DHA), a polyunsaturated ω-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca2+- and voltage-gated Slo1 BK channels are directly activated by nanomolar levels of DHA. We investigated DHA-channel interaction by manipulating both the fatty acid structure and the channel composition through the site-directed incorporation of unnatural amino acids. Electrophysiological measurements show that the para-group of a Tyr residue near the ion conduction pathway has a critical role. To robustly activate the channel, ionization must occur readily by a fatty acid for a good efficacy, and a long nonpolar acyl tail with a Z double bond present at the halfway position for a high affinity. The results suggest that DHA and the channel form an ion-dipole bond to promote opening and demonstrate the channel druggability. DHA, a marine-derived nutraceutical, represents a promising lead compound for rational drug design and discovery.


Assuntos
Ácidos Docosa-Hexaenoicos/química , Ácidos Graxos Ômega-3/química , Ácidos Graxos Insaturados/química , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Insaturados/metabolismo , Ácidos Graxos Insaturados/uso terapêutico , Óleos de Peixe/química , Óleos de Peixe/metabolismo , Humanos , Ativação do Canal Iônico/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/química , Canais de Potássio Ativados por Cálcio de Condutância Alta/química , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo
6.
Hum Mol Genet ; 23(23): 6395-406, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24986916

RESUMO

We conducted blinded psychiatric assessments of 26 Amish subjects (52 ± 11 years) from four families with prevalent bipolar spectrum disorder, identified 10 potentially pathogenic alleles by exome sequencing, tested association of these alleles with clinical diagnoses in the larger Amish Study of Major Affective Disorder (ASMAD) cohort, and studied mutant potassium channels in neurons. Fourteen of 26 Amish had bipolar spectrum disorder. The only candidate allele shared among them was rs78247304, a non-synonymous variant of KCNH7 (c.1181G>A, p.Arg394His). KCNH7 c.1181G>A and nine other potentially pathogenic variants were subsequently tested within the ASMAD cohort, which consisted of 340 subjects grouped into controls subjects and affected subjects from overlapping clinical categories (bipolar 1 disorder, bipolar spectrum disorder and any major affective disorder). KCNH7 c.1181G>A had the highest enrichment among individuals with bipolar spectrum disorder (χ(2) = 7.3) and the strongest family-based association with bipolar 1 (P = 0.021), bipolar spectrum (P = 0.031) and any major affective disorder (P = 0.016). In vitro, the p.Arg394His substitution allowed normal expression, trafficking, assembly and localization of HERG3/Kv11.3 channels, but altered the steady-state voltage dependence and kinetics of activation in neuronal cells. Although our genome-wide statistical results do not alone prove association, cumulative evidence from multiple independent sources (parallel genome-wide study cohorts, pharmacological studies of HERG-type potassium channels, electrophysiological data) implicates neuronal HERG3/Kv11.3 potassium channels in the pathophysiology of bipolar spectrum disorder. Such a finding, if corroborated by future studies, has implications for mental health services among the Amish, as well as development of drugs that specifically target HERG3/Kv11.3.


Assuntos
Arginina/genética , Transtorno Bipolar/genética , Canais de Potássio Éter-A-Go-Go/genética , Histidina/genética , Adulto , Idoso , Amish , Transtorno Bipolar/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo
7.
Proc Natl Acad Sci U S A ; 110(12): 4822-7, 2013 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-23487786

RESUMO

Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels are well known for their functional versatility, which is bestowed in part by their rich modulatory repertoire. We recently showed that long-chain omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) found in oily fish lower blood pressure by activating vascular BK channels made of Slo1+ß1 subunits. Here we examined the action of DHA on BK channels with different auxiliary subunit compositions. Neuronal Slo1+ß4 channels were just as well activated by DHA as vascular Slo1+ß1 channels. In contrast, the stimulatory effect of DHA was much smaller in Slo1+ß2, Slo1+LRRC26 (γ1), and Slo1 channels without auxiliary subunits. Mutagenesis of ß1, ß2, and ß4 showed that the large effect of DHA in Slo1+ß1 and Slo1+ß4 is conferred by the presence of two residues, one in the N terminus and the other in the first transmembrane segment of the ß1 and ß4 subunits. Transfer of this amino acid pair from ß1 or ß4 to ß2 introduces a large response to DHA in Slo1+ß2. The presence of a pair of oppositely charged residues at the aforementioned positions in ß subunits is associated with a large response to DHA. The Slo1 auxiliary subunits are expressed in a highly tissue-dependent fashion. Thus, the subunit composition-dependent stimulation by DHA demonstrates that BK channels are effectors of omega-3 fatty acids with marked tissue specificity.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Complexos Multiproteicos/metabolismo , Subunidades Proteicas/metabolismo , Células HEK293 , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Complexos Multiproteicos/genética , Mutagênese , Especificidade de Órgãos/fisiologia , Estrutura Terciária de Proteína , Subunidades Proteicas/genética
8.
Proc Natl Acad Sci U S A ; 110(12): 4816-21, 2013 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-23487785

RESUMO

Long-chain polyunsaturated omega-3 fatty acids such as docosahexaenoic acid (DHA), found abundantly in oily fish, may have diverse health-promoting effects, potentially protecting the immune, nervous, and cardiovascular systems. However, the mechanisms underlying the purported health-promoting effects of DHA remain largely unclear, in part because molecular signaling pathways and effectors of DHA are only beginning to be revealed. In vascular smooth muscle cells, large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels provide a critical vasodilatory influence. We report here that DHA with an EC50 of ∼500 nM rapidly and reversibly activates BK channels composed of the pore-forming Slo1 subunit and the auxiliary subunit ß1, increasing currents by up to ∼20-fold. The DHA action is observed in cell-free patches and does not require voltage-sensor activation or Ca(2+) binding but involves destabilization of the closed conformation of the ion conduction gate. DHA lowers blood pressure in anesthetized wild-type but not in Slo1 knockout mice. DHA ethyl ester, contained in dietary supplements, fails to activate BK channels and antagonizes the stimulatory effect of DHA. Slo1 BK channels are thus receptors for long-chain omega-3 fatty acids, and these fatty acids--unlike their ethyl ester derivatives--activate the channels and lower blood pressure. This finding has practical implications for the use of omega-3 fatty acids as nutraceuticals for the general public and also for the critically ill receiving omega-3-enriched formulas.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Knockout , Estrutura Terciária de Proteína
9.
Artigo em Inglês | MEDLINE | ID: mdl-38498742

RESUMO

Depression is one of the most serious mental disorders affecting modern human life and is often caused by chronic stress. Dopamine system dysfunction is proposed to contribute to the pathophysiology of chronic stress, especially the ventral tegmental area (VTA) which mainly consists of dopaminergic neurons. Focused ultrasound stimulation (FUS) is a promising neuromodulation modality and multiple studies have demonstrated effective ultrasonic activation of cortical, subcortical, and related networks. However, the effects of FUS on the dopamine system and the potential link to chronic stress-induced depressive behaviors are relatively unknown. Here, we measured the effects of FUS targeting VTA on the improvement of depression-like behavior and evaluated the dopamine concentration in the downstream region - medial prefrontal cortex (mPFC). We found that targeting VTA FUS treatment alleviated chronic restraint stress (CRS) -induced anhedonia and despair behavior. Using an in vivo photometry approach, we analyzed the dopamine signal of mPFC and revealed a significant increase following the FUS, positively associated with the improvement of anhedonia behavior. FUS also protected the dopaminergic neurons in VTA from the damage caused by CRS exposure. Thus, these results demonstrated that targeting VTA FUS treatment significantly rescued the depressive-like behavior and declined dopamine level of mPFC induced by CRS. These beneficial effects of FUS might be due to protection in the DA neuron of VTA. Our findings suggest that FUS treatment could serve as a new therapeutic strategy for the treatment of stress-related disorders.


Assuntos
Anedonia , Dopamina , Humanos , Córtex Pré-Frontal/fisiologia , Área Tegmentar Ventral/fisiologia , Neurônios/fisiologia , Neurônios Dopaminérgicos/fisiologia
10.
Sheng Wu Gong Cheng Xue Bao ; 39(10): 4029-4045, 2023 Oct 25.
Artigo em Zh | MEDLINE | ID: mdl-37877388

RESUMO

Mechanosensitive channels (MSCs) are special membrane proteins that can convert mechanical stimulation into electrical or chemical signals. These channels have become potential targets for ultrasonic neuromodulation due to their properties. The good spatial resolution and focusing effect of ultrasound make it theoretically possible to achieve non-invasive whole-brain localization. Therefore, ultrasonic neuromodulation is a promising method for performing physical neuromodulation and treating neurological disorders. To date, only a few ion channels have been reported to be activated by ultrasound, while recent research has identified more channels with mechanosensitive properties. Moreover, the opening process and mechanism of MSCs under ultrasound excitation remain unknown. This review provides an overview on recent research advances and applications in MSCs, including large conductance mechanosensitive channels, transient receptor potential channels, degenerated protein/epithelial sodium channels, two-pore potassium channels, and piezo channels. These findings will facilitate future studies and applications of ultrasonic neuromodulation.


Assuntos
Canais Iônicos , Ultrassom , Canais Iônicos/metabolismo
11.
Front Aging Neurosci ; 14: 814560, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35264943

RESUMO

Working memory impairment is one of the remarkable cognitive dysfunctions induced by vascular dementia (VD), and it is necessary to explore an effective treatment. Recently, low-intensity focused ultrasound stimulation (LIFUS) has been found notable neuroprotective effects on some neurological diseases, including VD. However, whether it could ameliorate VD-induced working memory impairment was still not been clarified. The purpose of this study was to address this issue and the underlying mechanism. We established VD rat model using the bilateral common carotid artery occlusion (BCCAO) and applied the LIFUS (center frequency = 0.5 MHz; Ispta = 500 mW/cm2, 10 mins/day) to bilateral medial prefrontal cortex (mPFC) for 2 weeks since 2 weeks after the surgery. The main results showed that the LIFUS could significantly improve the performance of VD rats in the specific working memory tasks (delayed nonmatch-to-sample task and step-down task), which might be associated with the improved synaptic function. We also found the improvement in the cerebral blood flow (CBF) and reduced neuroinflammation in mPFC after LIFUS treatment indicated by the inhibition of Toll-like receptor (TLR4)/nuclear factor kappa B (NF-κB) pathway and the decrease of proinflammatory cytokines. The amelioration of CBF and neuroinflammation may promote the living environment of the neurons in VD which then contribute to the survival of neurons and the improvement in synaptic function. Taken together, our findings indicate that LIFUS targeted mPFC can effectively ameliorate reward-based spatial working memory and fear working memory dysfunctions induced by VD via restoring the living environment, survivability, and synaptic functions of the neurons in mPFC of VD rats. This study adds to the evidence that LIFUS could become a promising and non-invasive treatment strategy for the clinical treatment of central nervous system diseases related to cognitive impairments in the future.

14.
Sheng Li Xue Bao ; 59(1): 63-70, 2007 Feb 25.
Artigo em Zh | MEDLINE | ID: mdl-17294044

RESUMO

The effects of beta-cypermethrin (consisting of alpha-cypermethrin and theta-cypermethrin) on the transient outward potassium current (I(A)) and delayed rectifier potassium current (I(K)) in freshly dissociated hippocampal CA3 neurons of rats were studied using whole-cell patch-clamp technique. The results indicated that alpha-cypermethrin increased the value of I(A) and theta-cypermethrin decreased the value of I(A), though both of them shifted steady activation curve of I(A) towards negative potential. theta-cypermethrin contributed to the inactivation of I(A). The results also showed that alpha-cypermethrin and theta-cypermethrin decreased the value of I(K), and shifted the steady state activation curve of I(K) towards negative potential. Both alpha-cypermethrin and theta-cypermethrin had no obvious effects on the inactivation of I(K). theta-cypermethrin prolonged recovery process of I(K). These results imply that both transient outward potassium channels and delayed rectified potassium channels are the targets of beta-cypermethrin, which may explain the mechanism of toxical effects of beta-cypermethrin on mammalian neurons.


Assuntos
Região CA3 Hipocampal/citologia , Neurônios/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Piretrinas/toxicidade , Animais , Região CA3 Hipocampal/fisiologia , Células Cultivadas , Feminino , Inseticidas/toxicidade , Masculino , Neurônios/citologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Ratos , Ratos Wistar
15.
J Gen Physiol ; 145(4): 331-43, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25825171

RESUMO

Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a critical role in modulating the function of numerous ion channels, including large-conductance Ca(2+)- and voltage-dependent K(+) (BK, Slo1) channels. Slo1 BK channel complexes include four pore-forming Slo1 (α) subunits as well as various regulatory auxiliary subunits (ß and γ) that are expressed in different tissues. We examined the molecular and biophysical mechanisms underlying the effects of brain-derived PIP2 on human Slo1 BK channel complexes with different subunit compositions that were heterologously expressed in human embryonic kidney cells. PIP2 inhibited macroscopic currents through Slo1 channels without auxiliary subunits and through Slo1 + γ1 complexes. In contrast, PIP2 markedly increased macroscopic currents through Slo1 + ß1 and Slo1 + ß4 channel complexes and failed to alter macroscopic currents through Slo1 + ß2 and Slo1 + ß2 Δ2-19 channel complexes. Results obtained at various membrane potentials and divalent cation concentrations suggest that PIP2 promotes opening of the ion conduction gate in all channel types, regardless of the specific subunit composition. However, in the absence of ß subunits positioned near the voltage-sensor domains (VSDs), as in Slo1 and probably Slo1 + γ1, PIP2 augments the negative surface charge on the cytoplasmic side of the membrane, thereby shifting the voltage dependence of VSD-mediated activation in the positive direction. When ß1 or ß4 subunits occupy the space surrounding the VSDs, only the stimulatory effect of PIP2 is evident. The subunit compositions of native Slo1 BK channels differ in various cell types; thus, PIP2 may exert distinct tissue- and divalent cation-dependent modulatory influences.


Assuntos
Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Sequência de Aminoácidos , Animais , Humanos , Ativação do Canal Iônico , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/química , Dados de Sequência Molecular , Ligação Proteica , Xenopus
17.
J Gen Physiol ; 142(5): 507-22, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24127525

RESUMO

Long-chain polyunsaturated omega-3 fatty acids such as docosahexaenoic acid (DHA) at nanomolar concentrations reversibly activate human large-conductance Ca(2+)- and voltage-gated K(+) (Slo1 BK) channels containing auxiliary ß1 or ß4 subunits in cell-free patches. Here we examined the action of DHA on the Slo1 channel without any auxiliary subunit and sought to elucidate the biophysical mechanism and the molecular determinants of the DHA sensitivity. Measurements of ionic currents through human Slo1 (hSlo1) channels reveal that the stimulatory effect of DHA does not require activation of the voltage or Ca(2+) sensors. Unlike gating of the hSlo1 channel, that of the Drosophila melanogaster Slo1 (dSlo1) channel is unaltered by DHA. Our mutagenesis study based on the differential responses of human and dSlo1 channels to DHA pinpoints that Y318 near the cytoplasmic end of S6 in the hSlo1 channel is a critical determinant of the stimulatory action of DHA. The mutation Y318S in hSlo1, which replaces Y with S as found in dSlo1, greatly diminishes the channel's response to DHA with a 22-carbon chain whether ß1 or ß4 is absent or present. However, the responses to α-linolenic acid, an omegea-3 fatty acid with an 18-carbon chain, and to arachidonic acid, an omega-6 fatty acid with a 20-carbon chain, remain unaffected by the mutation. Y318 in the S6 segment of hSlo1 is thus an important determinant of the electrophysiological response of the channel to DHA. Furthermore, the mutation Y318S may prove to be useful in dissecting out the complex lipid-mediated modulation of Slo1 BK channels.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Proteínas de Drosophila/genética , Ácidos Graxos Ômega-3/metabolismo , Ativação do Canal Iônico/fisiologia , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Potenciais da Membrana/fisiologia , Animais , Células Cultivadas , Ácidos Docosa-Hexaenoicos/farmacologia , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Ácidos Graxos Ômega-3/farmacologia , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Rim/citologia , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/química , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Alta/química , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Modelos Biológicos , Mutagênese Sítio-Dirigida , Mutação Puntual , Estrutura Terciária de Proteína/fisiologia
18.
Brain Res Bull ; 87(4-5): 420-6, 2012 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-22314371

RESUMO

Urethane is a widely used anesthetic for animal experiments. Although urethane is thought to minimally interfere with neurophysiological processes and appears to preserve synaptic signal transmission, it has also been reported to produce depressive effects on neuronal excitability. In the present study, we used electrophysiological recordings to investigate the effects of urethane on rat hippocampal CA1 neurons. Whole-cell recordings were employed in a brain slice preparation to record discharges in current-clamp mode and sEPSCs or mEPSCs in voltage-clamp mode. Urethane was found to significantly increase both the interspike interval and the coefficient of variation of the firing. Moreover, it was found that the inter-event intervals of sEPSC/mEPSCs were increased, but the amplitude and the kinetic properties (rise time and decay time) of the sEPSC/mEPSC were not altered by urethane, which implies that potassium leak currents were involved in such effects. The results suggest that urethane significantly suppresses activity of hippocampal CA1 neurons and alters spontaneous pre-synaptic glutamatergic release possibly by activating potassium leak currents.


Assuntos
Anestésicos Intravenosos/toxicidade , Região CA1 Hipocampal/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Canais de Potássio/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Uretana/toxicidade , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Masculino , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Wistar
19.
Int J Nanomedicine ; 6: 1453-61, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21796247

RESUMO

This study focused on the effects of zinc oxide nanoparticles (nano-ZnO) on spatial learning and memory and synaptic plasticity in the hippocampus of young rats, and tried to interpret the underlying mechanism. Rats were randomly divided into four groups. Nano-ZnO and phosphate-buffered saline were administered in 4-week-old rats for 8 weeks. Subsequently, performance in Morris water maze (MWM) was determined, and then long-term potentiation (LTP) and depotentiation were measured in the perforant pathway to dentate gyrus (DG) in anesthetized rats. The data showed that, (1) in MWM, the escape latency was prolonged in the nano-ZnO group and, (2) LTP was significantly enhanced in the nano-ZnO group, while depotentiation was barely influenced in the DG region of the nano-ZnO group. This bidirectional effect on long-term synaptic plasticity broke the balance between stability and flexibility of cognition. The spatial learning and memory ability was attenuated by the alteration of synaptic plasticity in nano-ZnO-treated rats.


Assuntos
Giro Denteado/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Nanopartículas Metálicas/química , Óxido de Zinco/farmacologia , Análise de Variância , Animais , Cognição/efeitos dos fármacos , Transtornos Cognitivos/induzido quimicamente , Giro Denteado/fisiologia , Estimulação Elétrica , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Memória/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Plasticidade Neuronal/efeitos dos fármacos , Via Perfurante , Distribuição Aleatória , Ratos , Ratos Wistar , Suspensões , Óxido de Zinco/química , Óxido de Zinco/toxicidade
20.
Brain Res Bull ; 85(3-4): 109-16, 2011 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-21396989

RESUMO

Growing evidence suggests the involvement of stress in the pathophysiology of depression. This study was designed to test behavioral and electrophysiological changes in a stressed model of depression. Rats were randomly divided into control and stressed groups. Chronic unpredictable stress combined with isolation rearing was applied in rats of stressed group for three weeks. Weight and sucrose consumption were measured during the model establishing period. Behavior was measured by Morris water maze. Electroencephalography (EEG) of thalamus and prefrontal cortex was recorded after behavioral tests, followed by recording long-term potentiation (LTP) of the same thalamocortical pathway. Results showed that rats' weight and sucrose intake were significantly lower in stressed group than those in control group. In stressed group, escape latency of reversal training stage in water maze test was significantly prolonged, and platform crossings of reversal probe trials were significantly decreased. EEG test showed that the extent of thalamus driving prefrontal cortex was decreased in stressed group. LTP test showed lower postsynaptic potential amplitude in stressed group as compared to that in control group. In conclusion, chronic stress could cause certain behavioral changes in rats, with possible mechanism of impairing EEG of certain thalamocortical pathway and prefrontal cortical synaptic plasticity.


Assuntos
Ondas Encefálicas/fisiologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Potenciação de Longa Duração/fisiologia , Estresse Psicológico/patologia , Tálamo/fisiopatologia , Análise de Variância , Animais , Peso Corporal , Modelos Animais de Doenças , Estimulação Elétrica/métodos , Eletroencefalografia/métodos , Privação de Alimentos , Masculino , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Wistar , Estresse Psicológico/fisiopatologia , Sacarose/metabolismo , Fatores de Tempo , Privação de Água
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA