scholarly journals Bursting in cerebellar stellate cells induced by pharmacological agents: Non-sequential spike adding

2020 ◽  
Vol 16 (12) ◽  
pp. e1008463
Author(s):  
Saeed Farjami ◽  
Ryan P. D. Alexander ◽  
Derek Bowie ◽  
Anmar Khadra
Keyword(s):  
Stellate Cells ◽  
Delayed Rectifier ◽  
Type Model ◽  
Type I ◽  
Low Doses ◽  
Pharmacological Agents ◽  
Whole Cell ◽  
Square Wave ◽  
Cell Configuration ◽  
High Doses

Cerebellar stellate cells (CSCs) are spontaneously active, tonically firing (5-30 Hz), inhibitory interneurons that synapse onto Purkinje cells. We previously analyzed the excitability properties of CSCs, focusing on four key features: type I excitability, non-monotonic first-spike latency, switching in responsiveness and runup (i.e., temporal increase in excitability during whole-cell configuration). In this study, we extend this analysis by using whole-cell configuration to show that these neurons can also burst when treated with certain pharmacological agents separately or jointly. Indeed, treatment with 4-Aminopyridine (4-AP), a partial blocker of delayed rectifier and A-type K+ channels, at low doses induces a bursting profile in CSCs significantly different than that produced at high doses or when it is applied at low doses but with cadmium (Cd2+), a blocker of high voltage-activated (HVA) Ca2+ channels. By expanding a previously revised Hodgkin–Huxley type model, through the inclusion of Ca2+-activated K+ (K(Ca)) and HVA currents, we explain how these bursts are generated and what their underlying dynamics are. Specifically, we demonstrate that the expanded model preserves the four excitability features of CSCs, as well as captures their bursting patterns induced by 4-AP and Cd2+. Model investigation reveals that 4-AP is potentiating HVA, inducing square-wave bursting at low doses and pseudo-plateau bursting at high doses, whereas Cd2+ is potentiating K(Ca), inducing pseudo-plateau bursting when applied in combination with low doses of 4-AP. Using bifurcation analysis, we show that spike adding in square-wave bursts is non-sequential when gradually changing HVA and K(Ca) maximum conductances, delayed Hopf is responsible for generating the plateau segment within the active phase of pseudo-plateau bursts, and bursting can become “chaotic” when HVA and K(Ca) maximum conductances are made low and high, respectively. These results highlight the secondary effects of the drugs applied and suggest that CSCs have all the ingredients needed for bursting.

Potassium currents in mammalian and avian isolated type I semicircular canal hair cells

1994 ◽  
Vol 71 (1) ◽  
pp. 317-329 ◽  
Author(s):  
K. J. Rennie ◽  
M. J. Correia
Keyword(s):  
Membrane Potential ◽  
Hair Cells ◽  
Potassium Current ◽  
Columba Livia ◽  
Membrane Properties ◽  
Delayed Rectifier ◽  
Type I ◽  
Type Ii ◽  
Current Clamp ◽  
Whole Cell

1. Type I vestibular hair cells were isolated from the cristae ampullares of the semicircular canals of the Mongolian gerbil (Meriones unguiculatus) and the white king pigeon (Columba livia). Dissociated type I cells were distinguished from type II hair cells by their neck to plate ratio (NPR) and their characteristic amphora shape. 2. The membrane properties of gerbil and pigeon type I hair cells were studied in whole-cell voltage- and current-clamp using the perforated patch technique with amphotericin B as the perforating agent. 3. In whole-cell current-clamp, the average zero-current potential, Vz, measured for pigeon type I hair cells, was -70 +/- 7 (SD) mV (n = 18) and -71 +/- 11 mV (n = 83) for gerbil type I hair cells. 4. At Vz, for both gerbil and pigeon type I hair cells, a potassium current (IKI) was > or = 50% activated. This current deactivated rapidly when the membrane potential was hyperpolarized below -90 mV. 5. IKI was blocked by externally applied 4-aminopyridine (4-AP) (5 mM) and by internally applied 20 mM tetraethylammonium (TEA). It was also reduced when 4 mM barium was present in the external solution. The degree of block by barium increased as the membrane potential became more positive. External cesium (5 mM) blocked the inward component of IKI. When IKI was pharmacologically blocked, Vz depolarized by approximately 40 mV. Therefore IKI appears to be a delayed rectifier and to set the more negative Vz noted for isolated type I hair cells when compared to isolated type II hair cells, which do not have IKI. 6. A second, smaller potassium current was present at membrane potential depolarizations above -40 mV. This current was blocked by 30-50 mM, externally applied TEA, 100 microM quinidine, 100 nM apamin, but not 100 nM charybdotoxin, indicating that this is a calcium-activated potassium current, IK(Ca), different from the maxi-K calcium-activated potassium current found in most other hair cells.

scholarly journals Serotonin regulates voltage-dependent currents in type Ie(A) and Ii interneurons of Hermissenda

2011 ◽  
Vol 106 (5) ◽  
pp. 2557-2569 ◽  
Author(s):  
Nan Ge Jin ◽  
Terry Crow
Keyword(s):  
Nervous System ◽  
Intrinsic Excitability ◽  
Delayed Rectifier ◽  
Inactivation Kinetics ◽  
Type I ◽  
Activation Curve ◽  
Inactivation Curve ◽  
Whole Cell ◽  
Different Types ◽  
Hyperpolarizing Shift

Serotonin (5-HT) has both direct and modulatory actions on central neurons contributing to behavioral arousal and cellular-synaptic plasticity in diverse species. In Hermissenda, 5-HT produces changes in intrinsic excitability of different types of identified interneurons in the circumesophageal nervous system. Using whole cell patch-clamp techniques we have examined membrane conductance changes produced by 5-HT that contribute to intrinsic excitability in two identified classes of interneurons, types Ii and IeA. Whole cell currents were examined before and after 5-HT application to the isolated nervous system. A 4-aminopyridine-sensitive transient outward K+ current [ IK(A)], a tetraethylammonium-sensitive delayed rectifier K+ current [ IK(V)], an inward rectifier K+ current [ IK(IR)], and a hyperpolarization-activated current ( Ih) were characterized. 5-HT decreased the amplitude of IK(A) and IK(V) in both type Ii and IeA interneurons. However, differences in 5-HT's effects on the activation-inactivation kinetics were observed in different types of interneurons. 5-HT produced a depolarizing shift in the activation curve of IK(V) and a hyperpolarizing shift in the inactivation curve of IK(A) in type Ii interneurons. In contrast, 5-HT produced a depolarizing shift in the activation curve and a hyperpolarizing shift in the inactivation curve of both IK(V) and IK(A) in type IeA interneurons. In addition, 5-HT decreased the amplitude of IK(IR) in type Ii interneurons and increased the amplitude of Ih in type IeA interneurons. These results indicate that 5-HT-dependent changes in IK(A), IK(V), IK(IR), and Ih contribute to multiple mechanisms that synergistically support modulation of increased intrinsic excitability associated with different functional classes of identified type I interneurons.

ANTAGONISTIC ACTION OF NORETHYNODREL ON THE TESTOSTERONE-DEPENDENT PROCESS OF FRUCTOSE FORMATION IN MOUSE SEX ACCESSORY ORGANS

1966 ◽  
Vol 51 (2) ◽  
pp. 224-230 ◽  
Author(s):  
John A. Thomas ◽  
Edward T. Knych
Keyword(s):  
Antagonistic Activity ◽  
Low Doses ◽  
Antagonistic Action ◽  
Dependent Process ◽  
High Doses

ABSTRACT Norethynodrel antagonized the fructose stimulating effects of exogenous testosterone in sex accessory organs of castrate mice. It was antiandrogenic at both low doses (50 μg) and high doses (400 μg) of testosterone. Norethindrone and ethisterone suppressed fructose formation in the testosterone-treated castrate mouse, but not as effectively as norethynodrel. Norethandrolone exerted no antagonistic activity.

scholarly journals Nuclear Cathepsin F Regulates Activation Markers in Rat Hepatic Stellate Cells

2008 ◽  
Vol 19 (10) ◽  
pp. 4238-4248 ◽  
Author(s):  
Gunter Maubach ◽  
Michelle Chin Chia Lim ◽  
Lang Zhuo
Keyword(s):  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Activation Process ◽  
Type I ◽  
Activation Markers ◽  
Nuclear Activity ◽  
Cystatin B ◽  
Cathepsin F

Activation of hepatic stellate cells during liver fibrosis is a major event facilitating an increase in extracellular matrix deposition. The up-regulation of smooth muscle α-actin and collagen type I is indicative of the activation process. The involvement of cysteine cathepsins, a class of lysosomal cysteine proteases, has not been studied in conjunction with the activation process of hepatic stellate cells. Here we report a nuclear cysteine protease activity partially attributed to cathepsin F, which co-localizes with nuclear speckles. This activity can be regulated by treatment with retinol/palmitic acid, known to reduce the hepatic stellate cell activation. The treatment for 48 h leads to a decrease in activity, which is coupled to an increase in cystatin B and C transcripts. Cystatin B knockdown experiments during the same treatment confirm the regulation of the nuclear activity by cystatin B. We demonstrate further that the inhibition of the nuclear activity by E-64d, a cysteine protease inhibitor, results in a differential regulation of smooth muscle α-actin and collagen type I transcripts. On the other hand, cathepsin F small interfering RNA transfection leads to a decrease in nuclear activity and a transcriptional down-regulation of both activation markers. These findings indicate a possible link between nuclear cathepsin F activity and the transcriptional regulation of hepatic stellate cell activation markers.

scholarly journals Antifertility Actions of a-Chlorohydrin in the Male

1983 ◽  
Vol 36 (4) ◽  
pp. 333 ◽  
Author(s):  
A RJones
Keyword(s):  
Male Fertility ◽  
Human Sperm ◽  
Male Rat ◽  
Low Doses ◽  
Dose Regime ◽  
Male Contraceptive ◽  
The Past ◽  
High Doses ◽  
Species Specific ◽  
Daily Oral Administration

Non-steroidal chemicals that affect male fertility have been known for over 25 years but only one compound, oc-chlorohydrin, possesses most of the attributes of an ideal male contraceptive. In the male rat, for example, continuous daily oral administration of low doses produces an almost immediate and continuous antifertility response that ceases when treatment is withdrawn. Such a dose regime does not interfere with libido, is apparently not toxic and the action is specific towards mature sperm. Furthermore, the action of the compound is species-specific: it is effective in the rat, ram, boar, guinea pig, hamster,rhesus monkey and upon ejaculated human sperm but it is ineffective in the mouse and the rabbit. High doses of oc-chlorohydrin can be neurotoxic, nephrotoxic and, in rats, lead to prolonged or permanent infertility. However, the antifertility response and the toxicity of racemic oc-chlorohydrin may be due, respectively, to the separate enantiomers. No other antifertility chemical has been investigated to such an extent as oc-chlorohydrin; this article reviews the progress that has been achieved with oc-chlorohydrin during the past six years.

Chloride channels in apical membrane patches of stellate cells of Malpighian tubules of Aedes aegypti

2001 ◽  
Vol 204 (2) ◽  
pp. 367-378 ◽  
Author(s):  
K.R. O'Connor ◽  
K.W. Beyenbach
Keyword(s):  
Aedes Aegypti ◽  
Apical Membrane ◽  
Stellate Cells ◽  
Malpighian Tubules ◽  
Type I ◽  
Open Probability ◽  
Cl Secretion ◽  
Cl Channel ◽  
Open Time ◽  
Channel Type

Stellate cells of Aedes aegypti Malpighian tubules were investigated using patch-clamp methods to probe the route of transepithelial Cl(−) secretion. Two types of Cl(−) channel were identified in excised, inside-out apical membrane patches. The first Cl(−) channel, type I, had a conductance of 24 pS, an open probability of 0.816+/−0.067, an open time of 867+/−114 ms (mean +/− s.e.m., four patches) and the selectivity sequence I(−)>Cl(−)(much greater than) isethionate>gluconate. The I(−)/Cl(−)>>isethionate>gluconate. The I(−)Cl(−) permeability ratio was 1.48, corresponding to Eisenman sequence I. The type I Cl(−) channel was blocked by 2,2′-iminodibenzoic acid (DPC) and niflumic acid (2-[3-(trifluoromethyl)anilo]nicotinic acid). The removal of Ca(2+) from the Ringer's solution on the cytoplasmic side had no effect on channel activity. The second Cl(−) channel, type II, had a conductance of 8 pS, an open probability of 0.066+/−0.021 and an open time of 7.53+/−1.46 ms (mean +/− s.e.m., four patches). The high density and halide selectivity sequence of the type I Cl(−) channel is consistent with a role in transepithelial Cl(−) secretion under control conditions, but it remains to be determined whether these Cl(−) channels also mediate transepithelial Cl(−) secretion under diuretic conditions in the presence of leucokinin.

A delayed rectifier conductance in type I hair cells of the mouse utricle

1996 ◽  
Vol 76 (2) ◽  
pp. 995-1004 ◽  
Author(s):  
A. Rusch ◽  
R. A. Eatock
Keyword(s):  
Hair Cells ◽  
Time Course ◽  
Dissociation Constants ◽  
Resting Potential ◽  
Delayed Rectifier ◽  
Type I ◽  
Type Ii ◽  
Voltage Range ◽  
Average Maximum

1. Membrane currents of hair cells in acutely excised or cultured mouse utricles were recorded with the whole cell voltage-clamp method at temperatures between 23 and 36 degrees C. 2. Type I and II hair cells both had delayed rectifier conductances that activated positive to -55 mV. 3. Type I, but not type II, hair cells had an additional delayed rectifier conductance (gK,L) with an activation range that was unusually negative and variable. At 23-25 degrees C, V(1/2) values ranged from -88 to -62 mV in 57 cells. 4. gK,L was very large. At 23-25 degrees C, the average maximum chord conductance was 75 +/- 65 nS (mean +/- SD, n = 57; measured at -54 mV), or approximately 21 nS/pF of cell capacitance. 5. gK,L was highly selective for K+ over Na+ (permeability ratio PNa+/PK+:0.006), but unlike other delayed rectifiers, gK,L was significantly permeable to Cs+ (PCs+/PK+:0.31). gK,L was independent of extracellular Ca2+. 6. At -64 mV, Ba2+ and 4-aminopyridine blocked gK,L with apparent dissociation constants of 2.0 mM and 43 microM, respectively. Extracellular Cs+ (5 mM) blocked gK,L by 50% at -124 mV. Apamin (100 nM) and dendrotoxin (10 nM) has no effect. 7. The kinetic data of gK,L are consistent with a sequential gating model with at least two closed states and one open state. The slow activation kinetics (principal time constants at 23-25 degrees C:600-200 ms) had a thermal Q10 of 2.1. Inactivation (Q10:2.7) was partial at all temperatures. Deactivation followed a double-exponential time course and had a Q10 of 2.0. 8. At 23-25 degrees C, gK,L was appreciably activated at the mean resting potential of type I hair cells (-77 +/- 3.1 mV, n = 62), so that input conductances were often more than an order of magnitude larger than those of type II cells. If these conditions hold in vivo, type I cells would produce unusually small receptor potentials. Warming the cells to 36 degrees C produced parallel shifts in gK,L's activation range (0.8 +/- 0.3 mV/degrees C, n = 8), and in the resting potential (0.6 +/- 0.3 mV/degrees C, n = 4). Thus the high input conductances were not an artifact of unphysiological temperatures but remained high near body temperature. It remains possible that in vivo gK,L's activation range is less negative and input conductances are lower; the large variance in the voltage range of activation suggests that it may be subject to modulation.

Differential Expression of Three Distinct Potassium Currents in the Ventral Cochlear Nucleus

2003 ◽  
Vol 89 (6) ◽  
pp. 3070-3082 ◽  
Author(s):  
Jason S. Rothman ◽  
Paul B. Manis
Keyword(s):  
Differential Expression ◽  
Cochlear Nucleus ◽  
Nerve Fibers ◽  
Delayed Rectifier ◽  
High Threshold ◽  
Type I ◽  
Acoustic Environment ◽  
Ventral Cochlear Nucleus ◽  
Wide Range ◽  
Slope Factor

In the ventral cochlear nucleus (VCN), neurons transform information from auditory nerve fibers into a set of parallel ascending pathways, each emphasizing different aspects of the acoustic environment. Previous studies have shown that VCN neurons differ in their intrinsic electrical properties, including the K+ currents they express. In this study, we examine these K+ currents in more detail using whole cell voltage-clamp techniques on isolated VCN cells from adult guinea pigs at 22°C. Our results show a differential expression of three distinct K+ currents. Whereas some VCN cells express only a high-threshold delayed-rectifier-like current ( IHT), others express IHT in combination with a fast inactivating current ( IA) and/or a slow-inactivating low-threshold current ( ILT). IHT, ILT, and IA, were partially blocked by 1 mM 4-aminopyridine. In contrast, only ILT was blocked by 10–100 nM dendrotoxin-I. A surprising finding was the wide range of levels of ILT, suggesting ILT is expressed as a continuum across cell types rather than modally in a particular cell type. IA, on the other hand, appears to be expressed only in cells that show little or no ILT, the Type I cells. Boltzmann analysis shows IHT activates with 164 ± 12 (SE) nS peak conductance, -14.3 ± 0.7 mV half-activation, and 7.0 ± 0.5 mV slope factor. Similar analysis shows ILT activates with 171 ± 22 nS peak conductance, -47.4 ± 1.0 mV half-activation, and 5.8 ± 0.3 mV slope factor.

Gastrointestinal motor effects of erythromycin

1990 ◽  
Vol 259 (3) ◽  
pp. G355-G363 ◽  
Author(s):  
M. F. Otterson ◽  
S. K. Sarna
Keyword(s):  
Small Intestine ◽  
Cycle Length ◽  
Amplitude Ratio ◽  
Contractile Activity ◽  
Low Doses ◽  
Control Activity ◽  
Distal Small Intestine ◽  
Gastrointestinal Motor ◽  
High Doses ◽  
Motor Effects

We studied the small intestinal motor effects of oral and intravenous (iv) erythromycin in 10 conscious dogs. After control recordings with placebo, oral or iv erythromycin was given at 40% of the migrating motor complex (MMC) cycle. Recordings were made after administration until normal contractile activity had returned or 12 h postdrug administration. Low doses initiated a premature MMC. High doses, however, prolonged the MMC cycle length. Erythromycin reduced the MMC propagation velocity at all doses. Both oral and iv erythromycin induced amyogenesia. During this pattern, electrical control activity was obliterated in the proximal and destabilized in the distal small intestine. Erythromycin also increased the incidence of retrograde giant contractions (RGCs) and vomiting. These effects occurred within the first 2 h after oral and within the first 30 min after iv administration. The incidence of giant migrating contractions (GMCs) increased significantly from 5 to 12 h but not from 0 to 5 h after administration. The distance of origination of GMCs from the ileocolonic junction was significantly increased from 5 to 12 h. The amplitude ratio, duration, and velocity of migration of GMCs induced after erythromycin were similar to control values. Clusters of coordinated antral and duodenal contractions also occurred early after administration. Our findings suggest that erythromycin has multiple motor effects on the stomach and small intestine. Diarrhea, abdominal cramping, and vomiting associated with erythromycin may be related to increased incidence of GMCs and RGCs. Erythromycin has a biphasic effect on MMC cycle length, initiating premature MMCs at low doses and prolonging their cycle length at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

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