scholarly journals Reversible Slow Desensitization of the Acid-Sensing Ion Channel (ASIC) 1a

2021 ◽  
Author(s):  
Margarita S Komarova ◽  
Andrey R Bukharev ◽  
Natalia N Potapieva ◽  
Denis B Tikhonov
Keyword(s):  
Steady State ◽  
Recovery Time ◽  
Time Course ◽  
Calcium Concentration ◽  
Response Amplitude ◽  
Progressive Decrease ◽  
Cell Recording ◽  
Ph Conditions ◽  
Different Origin

Abstract Among the proton-activated channels of the ASIC family, ASIC1a exhibits a specific tachyphylaxis phenomenon in the form of a progressive decrease in the response amplitude during a series of activations. This process is well known, but its mechanism is poorly understood. Here, we demonstrated a partial reversibility of this effect by long-term whole-cell recording of CHO cells transfected with rASIC1a cDNA. Long but infrequent acidifications provided the same recovery time course as short acidifications of the same frequency. Steady-state desensitization is not related to the slow desensitization and attenuates the development of the slow desensitization. Consequently, we found that drugs, which facilitate ASIC1a activation (e.g., amitriptyline), cause an enhancement of slow desensitization, while inhibition of ASIC1a by 9-aminoacridine attenuates the slow desensitization. In summary, for influences of vastly different origin, including increase of calcium concentration, different pH conditions, and action of modulating drugs, we found a correlation between the effect on response amplitude and on development of slow desensitization. Thus, our results prove that a slow desensitization requires the open ion-permeable state.

scholarly journals Regulation of intracellular cyclic GMP concentration by light and calcium in electropermeabilized rod photoreceptors.

1994 ◽  
Vol 103 (1) ◽  
pp. 67-86 ◽  
Author(s):  
V J Coccia ◽  
R H Cote
Keyword(s):  
Steady State ◽  
Guanylate Cyclase ◽  
Time Course ◽  
Calcium Concentration ◽  
Fold Increase ◽  
Photoreceptor Cells ◽  
Cyclase Activity ◽  
Free Calcium ◽  
Guanylate Cyclase Activity ◽  
Steady State Levels

This study examines the regulation of cGMP by illumination and by calcium during signal transduction in vertebrate retinal photoreceptor cells. We employed an electropermeabilized rod outer segment (EP-ROS) preparation which permits perfusion of low molecular weight compounds into the cytosol while retaining many of the features of physiologically competent, intact rod outer segments (ROS). When nucleotide-depleted EP-ROS were incubated with MgGTP, time- and dose-dependent increases in intracellular cGMP levels were observed. The steady state cGMP concentration in EP-ROS (0.007 mol cGMP per mol rhodopsin) approached the cGMP concentration in intact ROS. Flash illumination of EP-ROS in a 250-nM free calcium medium resulted in a transient decrease in cGMP levels; this occurred in the absence of changes in calcium concentration. The kinetics of the cGMP response to flash illumination of EP-ROS were similar to that of intact ROS. To further examine the effects of calcium on cGMP metabolism, dark-adapted EP-ROS were incubated with MgGTP containing various concentrations of calcium. We observed a twofold increase in cGMP steady state levels as the free calcium was lowered from 1 microM to 20 nM; this increase was comparable to the behavior of intact ROS. Measurements of guanylate cyclase activity in EP-ROS showed a 3.5-fold increase in activity over this range of calcium concentrations, indicating a retention of calcium regulation of guanylate cyclase in EP-ROS preparations. Flash illumination of EP-ROS in either a 50- or 250-nM free calcium medium revealed a slowing of the recovery time course at the lower calcium concentration. This observation conflicts with any hypothesis whereby a reduction in free calcium concentration hastens the recovery of cytoplasmic cGMP levels, either by stimulating guanylate cyclase activity or by inhibiting phosphodiesterase activity. We conclude that changes in the intracellular calcium concentration during visual transduction may have more complex effects on the recovery of the photoresponse than can be accounted for solely by guanylate cyclase activation.

scholarly journals Long-term repopulating hematopoietic stem cells and “side population” in human steady state peripheral blood

2013 ◽  
Vol 11 (1) ◽  
pp. 625-633 ◽  
Author(s):  
Philippe Brunet de la Grange ◽  
Marija Vlaski ◽  
Pascale Duchez ◽  
Jean Chevaleyre ◽  
Veronique Lapostolle ◽  
...  
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Side Population ◽  
Hematopoietic Stem

scholarly journals Selective Induction of LTP and LTD by Postsynaptic [Ca2+]i Elevation

1999 ◽  
Vol 81 (2) ◽  
pp. 781-787 ◽  
Author(s):  
Shao-Nian Yang ◽  
Yun-Gui Tang ◽  
Robert S. Zucker
Keyword(s):  
Calcium Concentration ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Biological Information ◽  
Synaptic Modulation ◽  
Ca1 Pyramidal Cells ◽  
Caged Calcium ◽  
Term Potentiation ◽  
Calcium Compound

Selective Induction of LTP and LTD by Postsynaptic [Ca2+]i Elevation. Long-term potentiation (LTP) and long-term depression (LTD), two prominent forms of synaptic plasticity at glutamatergic afferents to CA1 hippocampal pyramidal cells, are both triggered by the elevation of postsynaptic intracellular calcium concentration ([Ca2+]i). To understand how one signaling molecule can be responsible for triggering two opposing forms of synaptic modulation, different postsynaptic [Ca2+]i elevation patterns were generated by a new caged calcium compound nitrophenyl-ethylene glycol-bis(β-aminoethyl ether)- N, N, N′, N′-tetraacetic acid in CA1 pyramidal cells. We found that specific patterns of [Ca2+]i elevation selectively activate LTP or LTD. In particular, only LTP was triggered by a brief increase of [Ca2+]i with relatively high magnitude, which mimics the [Ca2+]i rise during electrical stimulation typically used to induce LTP. In contrast, a prolonged modest rise of [Ca2+]i reliably induced LTD. An important implication of the results is that both the amplitude and the duration of an intracellular chemical signal can carry significant biological information.

Time-course of treatment-emergent adverse events in a long-term safety study of lisdexamfetamine dimesylate in children and adolescents with ADHD

2016 ◽  
Vol 33 (S1) ◽  
pp. S132-S132
Author(s):  
I. Hernández Otero ◽  
T. Banaschewski ◽  
P. Nagy ◽  
C.A. Soutullo ◽  
A. Zuddas ◽  
...  
Keyword(s):  
Adverse Events ◽  
Children And Adolescents ◽  
Time Course ◽  
Open Label ◽  
Lisdexamfetamine Dimesylate ◽  
Safety Population ◽  
First Onset ◽  
Stimulant Medications ◽  
Competing Interest

IntroductionThe long-term safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention deficit/hyperactivity disorder (ADHD) was evaluated in a European 2-year, open-label study (SPD489-404).ObjectiveTo evaluate the time-course of treatment-emergent adverse events (TEAEs) in SPD489-404.MethodsParticipants aged 6–17 years received open-label LDX (30, 50 or 70 mg/day) for 104 weeks (4 weeks dose-optimization; 100 weeks dose-maintenance).ResultsAll enrolled participants (n = 314) were included in the safety population and 191 (60.8%) completed the study. TEAEs occurred in 282 (89.8%) participants; most were mild or moderate. TEAEs considered by the investigators as related to LDX were reported by 232 (73.9%) participants with the following reported for ≥ 10% of participants: decreased appetite (49.4%), weight decreased (18.2%), insomnia (13.1%). TEAEs leading to discontinuation and serious TEAEs occurred in 39 (12.4%) and 28 (8.9%) participants, respectively. The median (range) time to first onset and duration, respectively, of TEAEs identified by the sponsor as being of special interest were: insomnia (insomnia, initial insomnia, middle insomnia, terminal insomnia), 17.0 (1–729) and 42.8 (1–739) days; weight decreased, 29.0 (1–677) and 225.0 (26–724) days; decreased appetite, 13.5 (1–653) and 169.0 (1–749) days; headache, 22.0 (1–718) and 2.0 (1–729) days. Reports of insomnia, weight decreased, decreased appetite and headache were highest in the first 4–12 weeks.ConclusionsTEAEs associated with long-term LDX treatment were characteristic of stimulant medications, with the greatest incidence observed during the first 4–12 weeks.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Inward rectification in rat nucleus accumbens neurons

1989 ◽  
Vol 62 (6) ◽  
pp. 1280-1286 ◽  
Author(s):  
N. Uchimura ◽  
E. Cherubini ◽  
R. A. North
Keyword(s):  
Steady State ◽  
Nucleus Accumbens ◽  
Time Course ◽  
Potassium Conductance ◽  
Resting Potential ◽  
Inward Rectification ◽  
Resting Membrane Potential ◽  
Potential Range ◽  
Inward Current ◽  
Rat Nucleus Accumbens

1. Intracellular recordings were made from neurons in slices cut from the rat nucleus accumbens septi. Membrane currents were measured with a single-electrode voltage-clamp amplifier in the potential range -50 to -140 mV. 2. In control conditions (2.5 mM potassium), the resting membrane potential of the neurons was -83.4 +/- 1.1 (SE) mV (n = 157). Steady state membrane conductance was voltage dependent, being 34.8 +/- 1.7 nS (n = 25) at -100 mV and 8.0 +/- 0.7 nS (n = 25) at -60 mV. 3. Barium (1 microM) markedly reduced the inward rectification and caused a small inward current (40.6 +/- 8.7 pA, n = 8) at the resting potential. These effects became larger with higher barium concentrations, and, in 100 microM barium, the current-voltage relation was straight. 4. The block of the inward current by barium (at -130 mV) occurred with an exponential time course; the time constant was approximately 1 s at 1 microM barium and less than 90 ms with 100 microM. Strontium had effects similar to those of barium, but 1000-fold higher concentrations were required. Cesium chloride (2 mM) and rubidium chloride (2 mM) also blocked the inward rectification; their action reached steady state within 50 ms. 5. It is concluded that the nucleus accumbens neurons have a potassium conductance with many features of a typical inward rectifier and that this contributes to the potassium conductance at the resting potential.

Time Course of Expression of “Early” Genes during Long-Term Posttetanic Potentiation in Rat Hippocampal CA1 Field

2009 ◽  
Vol 148 (3) ◽  
pp. 416-418 ◽  
Author(s):  
O. O. Sokolova ◽  
M. B. Shtark ◽  
P. D. Lisachev ◽  
V. O. Pustyl’nyak ◽  
I. V. Pan
Keyword(s):  
Time Course ◽  
Posttetanic Potentiation ◽  
Early Genes ◽  
Hippocampal Ca1 ◽  
Hippocampal Ca1 Field

scholarly journals Central Insulin Signaling Is Attenuated by Long-Term Insulin Exposure via Insulin Receptor Substrate-1 Serine Phosphorylation, Proteasomal Degradation, and Lysosomal Insulin Receptor Degradation

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Christopher M. Mayer ◽  
Denise D. Belsham
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Time Course ◽  
Proteasomal Degradation ◽  
Serine Phosphorylation ◽  
Neuronal Function ◽  
Protein Levels ◽  
Phosphorylated Akt

Abstract Central insulin signaling is critical for the prevention of insulin resistance. Hyperinsulinemia contributes to insulin resistance, but it is not yet clear whether neurons are subject to cellular insulin resistance. We used an immortalized, hypothalamic, clonal cell line, mHypoE-46, which exemplifies neuronal function and expresses the components of the insulin signaling pathway, to determine how hyperinsulinemia modifies neuronal function. Western blot analysis indicated that prolonged insulin treatment of mHypoE-46 cells attenuated insulin signaling through phospho-Akt. To understand the mechanisms involved, time-course analysis was performed. Insulin exposure for 4 and 8 h phosphorylated Akt and p70-S6 kinase (S6K1), whereas 8 and 24 h treatment decreased insulin receptor (IR) and IR substrate 1 (IRS-1) protein levels. Insulin phosphorylation of S6K1 correlated with IRS-1 ser1101 phosphorylation and the mTOR-S6K1 pathway inhibitor rapamycin prevented IRS-1 serine phosphorylation. The proteasomal inhibitor epoxomicin and the lysosomal pathway inhibitor 3-methyladenine prevented the degradation of IRS-1 and IR by insulin, respectively, and pretreatment with rapamycin, epoxomicin, or 3-methyladenine prevented attenuation of insulin signaling by long-term insulin exposure. Thus, a sustained elevation of insulin levels diminishes neuronal insulin signaling through mTOR-S6K1-mediated IRS-1 serine phosphorylation, proteasomal degradation of IRS-1 and lysosomal degradation of the IR.

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