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PubMed2000

[Contribution of cochlear nucleus to 80Hz amplitude-modulation following response].

The steady-state response (SSR) evoked by a sinusoidally amplitude-modulated (SAM) tone is known as an amplitude-modulation following response (AMFR). The amplitude of the SSR which is elicited using clicks or tone bursts at a stimulus rate of 40 Hz, decreases during sleep. The same trend is also observed for AMFR at a modulation rate of 40 Hz. Thus it was difficult to analyzing SSR and AMFR is therefore difficult in young children, since objective audiometry just be performed while the child is asleep. Recent reports, however, have announced that the AMFR can be clearly detected at higher MFs (modulation frequencies), especially at frequencies between 80 and 100 Hz. This finding has proven useful in objective audiometry for young children. Recent reports have also suggested that AMFRs arise from multiple sources, including the auditory cortex and auditory nuclei in the brainstem. However, the exact sources of AMFRs have not been clarified. The purpose of this study is to clarify the contribution of the cochlear nucleus in evoking AMFRs at a modulation frequency of 80 Hz. The near-field potentials elicited with a SAM tone were recorded from the ipsilateral cochlear nucleus and its vicinity in cats. The near-field potential recorded by bipolar electrodes consisted of two different components: a low frequency component similar to the stimulus envelope (modulation), and a high frequency component similar to the actual stimulus tone. A sequence of field potentials was recorded using monopolar electrodes located at different sites within the cochlear nucleus and in its vicinity and on the surface of the cerebellum to confirm that near-field potentials elicited by SAM tones at a MF of 80 Hz in the cochlear nucleus can be recorded at the surface of the cerebellum or at other brain sites. The phase of the 80 Hz frequency component of the potentials elicited by a SAM tone at a MF of 80 Hz was then analyzed using a fast Fourier transformation. A contour map was produced using the means of the Fourier component phases corresponding to the 80 Hz response. The contour lines showed a rapid change in the phases recorded near the cochlear nucleus. These findings suggest that the cochlear nucleus contributes to the generation of scalp recorded AMFR at a MF of 80 Hz.

Acoustic Stimulation↗
PubMed2001

Receptor modulation by Fc gamma RI-specific fusion proteins is dependent on receptor number and modified by IgG.

The high-affinity IgG receptor, FcgammaRI (CD64), is constitutively expressed exclusively on professional APCs. Human FcgammaRI binds monomeric IgG with high affinity and is, therefore, saturated in vivo. The binding of IgG to FcgammaRI causes receptor recycling, while Abs that cross-link FcgammaRI cause rapid down-modulation of surface FcgammaRI. Because studies performed in the absence of ligand may not be representative of FcgammaRI modulation in vivo, we investigated the ability of FcgammaRI-cross-linking Abs and non-cross-linking derivatives to modulate FcgammaRI in the presence and absence of ligand. In the absence of ligand mAb H22 and wH22xeGFP, an enhanced green fluorescent protein (eGFP)-labeled fusion protein of H22, cross-linked and rapidly down-modulated surface FcgammaRI on the human myeloid cell line, U937, and its high FcgammaRI-expressing subclone, 10.6. This effect was dependent on the concentration of fusion protein and the level of FcgammaRI expression and correlated with internalization of both wH22xeGFP and FcgammaRI, itself, as assessed by confocal microscopy. A single-chain Fv version, sFv22xeGFP, which does not cross-link FcgammaRI, was unable to modulate FcgammaRI in the absence of IgG. However, if ligand was present, treatment with either monovalent or cross-linking fusion protein led to intracellular receptor accumulation. These findings suggest at least two alternate mechanisms of internalization that are influenced by ligand and demonstrate the physiologic potential of FcgammaRI to transport a large antigenic load into APCs for processing. These studies may lead to the development of better FcgammaRI-targeted vaccines, as well as therapies to down-modulate FcR involved in autoimmune diseases.

Adjuvants, Immunologic↗
PubMed1998

Biological effects of amplitude-modulated radiofrequency radiation.

Users of mobile telephones are exposed to radiofrequency radiation. One of the questions still open today is whether amplitude-modulated radiofrequency signals from digital phones exert specific bioeffects different from those of continuous (unmodulated) radiofrequency radiation. This paper reviews recent literature on the bioeffects of amplitude-modulated radiofrequency radiation, from cells to humans. The consistency of the results is discussed, and exposure parameters are compared to identify possible biologically active forms of amplitude modulation. Several studies have reported findings consistent with effects on the nervous system and cancer-related biological processes. However, the methods and exposure parameters vary widely, and no independent replications of the positive findings have been reported. The results available today fail to support the existence of well-defined modulation-specific bioeffects from exposure to radiofrequency radiation. Additional systematic studies are needed to identify possible reproducible modulation-dependent effects and biologically active modulation parameters.

Animals↗
PubMed2002

Receptor for activated C kinase-1 facilitates protein kinase C-dependent phosphorylation and functional modulation of GABA(A) receptors with the activation of G-protein-coupled receptors.

GABA(A) receptors are the principal sites of fast synaptic inhibition in the brain. These receptors are hetero-pentamers that can be assembled from a number of subunit classes: alpha(1-6), beta(1-3), gamma(1-3), delta(1), epsilon, theta;, and pi, but the majority of receptor subtypes is believed, however, to be composed of alpha, beta, and gamma2 subunits. A major mechanism for modulating GABA(A) receptor function occurs via the phosphorylation of residues within the intracellular domains of receptor subunits by a range of serine/threonine and tyrosine kinases. However, how protein kinases are targeted to these receptors to facilitate functional modulation remains unknown. Here we demonstrate that the receptor for activated C kinase (RACK-1) and protein kinase C (PKC) bind to distinct sites on GABA(A) receptor beta subunits. Although RACK-1 is not essential for PKC binding to GABA(A) receptor beta subunits, it enhances the phosphorylation of serine 409, a residue critical for the phospho-dependent modulation of GABA(A) receptor function in the beta1 subunit by anchored PKC. Furthermore, RACK-1 also enhances GABA(A) receptor functional modulation in neurons by a PKC-dependent signaling pathway with the activation of muscarinic acetylcholine receptors (mAChRs). This PKC-dependent modulation of neuronal GABA(A) receptors was mirrored by an increase in the phosphorylation of GABA(A) receptor beta subunits with the activation of mAChRs. Our results suggest a central role for RACK-1 in potentiating PKC-dependent phosphorylation and functional modulation of GABA(A) receptors. Therefore, RACK-1 will enhance functional cross talk between GABA(A) receptors and G-protein-coupled receptors and therefore may have profound effects on neuronal excitability.

Animals↗
PubMed1999

A new coiled hollow-fiber module design for enhanced microfiltration performance in biotechnology.

The microfiltration performance of a novel membrane module design with helically wound hollow fibers is compared with that obtained with a standard commercial-type crossflow module containing linear hollow fibers. Cell suspensions (yeast, E. coli, and mammalian cell cultures) commonly clarified in the biotechnology industry are used for this comparison. The effect of variables such as transmembrane pressure, particle suspension concentration, and feed flow rate on membrane performance is evaluated. Normalized permeation fluxes versus flow rate or Dean number behave according to a heat transfer correlation obtained with centrifugal instabilities of the Taylor type. The microfiltration performance of this new module design, which uses secondary flows in helical tubes, is significantly better than an equivalent current commercial crossflow module when filtering suspensions relevant to the biotechnology industry. Flux and capacity improvements of up to 3.2-fold (constant transmembrane pressure operation) and 3.9-fold (constant flux operation), respectively, were obtained with the helical module over those for the linear module.

Biotechnology↗
PubMed1999

Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids.

Gamma-aminobutyric acid type C receptor channels (GABA(C)Rs) composed of rho subunits are pharmacologically distinct from GABA(A) receptor channels (GABA(A)Rs). This difference is illustrated by the insensitivity of homo-oligomeric rho(1) receptor channels to many known modulators of GABA(A)Rs, such as barbiturates and benzodiazepines. A number of endogenous metabolites of corticosterone and progesterone, known as neuroactive steroids, compose yet another class of compounds that can modulate GABA(A)Rs. Here, several neuroactive steroids are shown to also modulate the rho(1) receptor channel. 5alpha-Pregnane-3alpha,21-diol-20-one (allotetrahydrodeoxycorticosterone), 5alpha-pregnane-3alpha-ol-11, 20-dione (alphaxalone), and 5alpha-pregnane-3alpha-ol-20-one (allopregnanolone) potentiated the GABA-evoked currents from rho(1) receptor channels and concomitantly altered the deactivation kinetics by prolonging the decay time. In contrast, 5beta-pregnane-3alpha-ol-20-one (pregnanolone), 5beta-pregnane-3, 20-dione (5beta-dihydroprogesterone), and 5beta-pregnane-3alpha, 21-diol-20-one (tetrahydrodeoxycorticosterone), all potentiators of GABA(A)Rs, inhibited the GABA-elicited currents of the rho(1) receptor channel. In comparison to GABA(A)Rs, the modulation of rho(1) receptor channels by these neuroactive compounds occurred with relatively high concentrations of the neuroactive steroids and was more prominent in the presence of low concentrations of GABA, equivalent to fractions of the EC(50) value of the rho(1) receptor channel. Structural comparison of these six neuroactive steroids reveals that the key parameter in determining the mode of modulation for the rho(1) receptor channel is the position of the hydrogen atom bound to the fifth carbon, imposing a trans- or cis-configuration in the backbone structure. This is the first demonstration of isomeric compounds that can differentially modulate the activity of the rho(1) receptor channel.

5-alpha-Dihydroprogesterone↗
PubMed2000

Independence of valence modulation and prepulse inhibition of startle.

This study sought to determine whether prepulse inhibition and valence modulation of startle are independent, both within and across individuals. Acoustic probes (105 dB) were delivered as 68 undergraduates viewed pleasant, neutral, and unpleasant pictures. Weak acoustic stimuli (8 dB above background) preceded half of the probes by 120 ms. As expected, startles were larger during unpleasant than during pleasant pictures, and smaller on prepulse than no-prepulse trials. In general, valence modulation and prepulse inhibition of startle were unrelated. That is, prepulse inhibition was consistent across affective states, valence modulation did not differ between no-prepulse and prepulse trials, and valence modulation and prepulse inhibition effects were uncorrelated across individuals. Analysis of raw and percent modification scores generally led to similar conclusions. It is concluded that valence modulation and prepulse inhibition are independent startle modulatory phenomena, although this conclusion is tempered by a finding of poor internal consistency reliability for valence modulation.

Acoustic Stimulation↗
PubMed2000

Retinal sensitivity to flicker modulation: reduced by early age-related maculopathy.

PURPOSE: To evaluate retinal, cone-mediated flicker sensitivity (CFS) in age-related maculopathy (ARM) by quantifying response gain and threshold of the focal electroretinogram (FERG) to flicker modulation. METHODS: Nineteen patients with ARM (visual acuity > or =20/30) and 11 age-matched control subjects were examined. Twelve patients had less than 20 soft drusen in the macular region and no hyper-/hypopigmentation (early lesion), whereas seven had more than 20 soft drusen and/or focal hyper-/hypopigmentation (advanced lesion). Macular (18 degree ) FERGs were elicited by a sinusoidally flickering (41 Hz) uniform field (on a light-adapting background) whose modulation depth was varied between 16.5% and 94%. Amplitude and phase of the response's fundamental harmonic were measured. RESULTS: In both control subjects and patients with ARM, log FERG amplitude increased with log stimulus modulation depth with a straight line (power law) relation. However, the slope (or gain) of the function was, on average, steeper in control subjects than in patients with either early or advanced lesions. Mean FERG threshold, estimated from the value of the log modulation depth that yielded a criterion response, did not differ between control subjects and patients with early lesions but was increased (0.35 log units) compared with control subjects in those with advanced lesions. In both patient groups, but not in control subjects, mean FERG phase tended to delay with decreasing stimulus modulation depth. CONCLUSIONS: Retinal CFS losses can be detected in ARM by evaluating the FERG as a function of flicker modulation depth. Reduced response gain and phase delays, with normal thresholds, are associated with early lesions. Increased response thresholds, in addition to gain and phase abnormalities, may reflect more advanced lesions. Evaluating CFS by FERG may directly document different stages of macular dysfunction in ARM.

Aged↗
PubMed2001

Cholinergic modulation of excitatory synaptic transmission in the CA3 area of the hippocampus.

Cholinergic innervation of the hippocampus has been implicated in memory formation and retrieval. Here we study cholinergic modulation of excitatory transmission in the CA3 area of the rat hippocampus. We used a combination of optical measurements of presynaptic calcium and electrophysiological measurements of synaptic currents to study associational-commissural (A/C) and mossy fiber (MF) synapses in brain slices. Direct synaptic modulation mediated by ACh receptors is only evident at the A/C synapse, where synaptic inhibition primarily reflects presynaptic calcium channel inhibition mediated by muscarinic receptors. MF synapses can, however, be indirectly modulated by muscarinic receptor activation. Muscarine elevates the firing rate of inhibitory cells, which increases GABA release and inhibits MF synapses by activating presynaptic GABA(B) receptors. Muscarine also depolarizes dentate granule cells and elevates their rate of firing. This leads to synaptic enhancement when combined with the use-dependent facilitation of MF synapses. In addition we were unable to evoke an increase in presynaptic calcium levels in MF boutons with local application of nicotinic receptor agonists. This finding does not support a leading hypothesis for MF modulation in which activation of presynaptic nicotinic receptors enhances transmission directly by elevating presynaptic calcium levels. However, indirect synaptic modulation could arise from nicotinic excitation of inhibitory neurons. Thus, to understand cholinergic modulation within the CA3 region, it is necessary to take into account secondary actions on synapses arising from other chemical messengers released by other cell types and to consider effects on firing patterns of presynaptic cells, which in turn influence release via use-dependent synaptic plasticity.

Animals↗
PubMed2001

High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer.

PURPOSE: We present the long-term outcome and tolerance of 3-dimensional (D) conformal and intensity modulated radiation therapy for localized prostate cancer. MATERIALS AND METHODS: Between October 1988 and December 1998, 1,100 patients with clinical stages T1c-T3 prostate cancer were treated with 3-D conformal or intensity modulated radiation therapy. Patients were categorized into prognostic risk groups based on pretreatment prostate specific antigen (PSA), Gleason score and clinical stage. Sextant biopsies were performed 2.5 years or greater after treatment to assess local control. PSA relapse was defined according to the consensus guidelines of the American Society for Therapeutic Radiation Oncology. Late toxicity was classified according to the Radiation Therapy Oncology Group morbidity grading scale. Median followup was 60 months. RESULTS: At 5 years the PSA relapse-free survival rate in patients at favorable, intermediate and unfavorable risk was 85% (95% confidence interval [CI] +/- 4), 58% (95% CI +/- 6) and 38% (95% CI +/- 6), respectively (p <0.001). Radiation dose was the most powerful variable impacting PSA relapse-free survival in each prognostic risk group. The 5-year actuarial PSA relapse-free survival rate for patients at favorable risk who received 64.8 to 70.2 Gy. was 77% (95% CI +/- 8) compared to 90% (95% CI +/- 8) for those treated with 75.6 to 86.4 Gy. (p = 0.04) [corrected]. The corresponding rates were 50% (95% CI +/- 8) versus 70% (95% CI +/- 6) in intermediate risk cases (p = 0.001), and 21% (95% CI +/- 8) versus 47% (95% CI +/- 6) in unfavorable risk cases (p = 0.008) [corrected]. Only 4 of 41 patients (10%) who received 81 Gy. had a positive biopsy 2.5 years or greater after treatment compared with 27 of 119 (23%) after 75.6, 23 of 68 (34%) after 70.2 and 13 of 24 (54%) after 64.8 Gy. The incidence of toxicity after 3-D conformal radiation therapy was dose dependent. The 5-year actuarial rate of grade 2 rectal toxicity in patients who received 75.6 Gy. or greater was 14% (95% CI +/- 2) compared with 5% (95% CI +/- 2) in those treated at lower dose levels (p <0.001). Treatment with intensity modulated radiation therapy significantly decreased the incidence of late grade 2 rectal toxicity since the 3-year actuarial incidence in 189 cases managed by 81 Gy. was 2% (95% CI +/- 2) compared with 14% (95% CI +/- 2) in 61 managed by the same dose of 3-D conformal radiation therapy (p = 0.005). The 5-year actuarial rate of grade 2 urinary toxicity in patients who received 75.6 Gy. or greater 3-D conformal radiation therapy was 13% compared with 4% in those treated up to lower doses (p <0.001). Intensity modulated radiation therapy did not affect the incidence of urinary toxicity. CONCLUSIONS: Sophisticated conformal radiotherapy techniques with high dose 3-D conformal and intensity modulated radiation therapy improve the biochemical outcome in patients with favorable, intermediate and unfavorable risk prostate cancer. Intensity modulated radiation therapy is associated with minimal rectal and bladder toxicity, and, hence, represents the treatment delivery approach with the most favorable risk-to-benefit ratio.

Adenocarcinoma↗
PubMedDate not supplied

[Geometrical model of spiral-cyclical self-organization of morphofunctional modules with two-dimensional (2D) transfer channels].

The general model of spiral-cyclic self-organization of morphofunctional modules has been studied with the help of elliptic Riemannian geometry. Depending on the level of hierarchy cells, groups of cells, macromolecules or subcellular components can function as separate biological units. The hierarchically coordinated morphofunctional modules of biological pattern with two-dimensional (2D) channels of morphogenes transfer are formed in the process of geometric transformation. The width of 2D channel is regulated by module parameters, whereas the direction of transport is controlled by vector of module electrostatic field. The disturbance of morphogenesis in the model is regarded as a change of reciprocal hierarchically coordinated arrangement of morphofunctional modules that causes branching of 2D channels without general power- and mass transfer. The model can be used for constructing concrete analogies of self-organization of morphofunctional modules in onto- and phylogenesis.

Animals↗
PubMed2001

Mass preparation of primary porcine hepatocytes and the design of a hybrid artificial liver module using spheroid culture for a clinical trial.

To isolate a large number of porcine hepatocytes, we originally developed a mass preparation method that combined the usual collagenase perfusion method of a whole liver with a collagenase redigestion method of tissue fragments after liver perfusion. Using a pig of 10kg, collagenase perfusion only resulted in a yield of 63+/-78 x 10(8) total cells with a viability of 69.2+/-25.3 %, but our combined method had a yield of 167+/-31 x 10(8) total cells with a viability of 87.9+/-4.4% (mean +/- SD). Also, the combined method was applied to two pigs of 10kg body weight at the same time, and isolated 387+/-89 x 10(8) hepatocytes with a viability of 87.1+/-6.9% and a purity of 93.6+/-2.8 % in 11 experiments. We designed a large multi-capillary polyurethane foam (MC-PUF) packed-bed module containing 1 x 10(10) porcine hepatocytes on a clinical trial scale. The porcine hepatocytes in the module formed spherical multicellular aggregates (spheroids) of 200 - 500 microm diameter. Most hepatocytes forming spheroids were viable judged by fluorescein diacetate and ethidium bromide staining. The activities of ammonia removal, albumin secretion and oxygen consumption of the large MC-PUF module were the same as for a small MC-PUF module containing 2 x 10(8) porcine hepatocytes, and were maintained for at least 9 days of culture. These results show that a large MC-PUF module is successfully scaled up 50 times. In conclusion, we succeeded in developing a mass preparation method of porcine hepatocytes and a large hybrid artificial liver module on a clinical trial scale.

Animals↗
PubMed2002

Attentional modulation of behavioral performance and neuronal responses in middle temporal and ventral intraparietal areas of macaque monkey.

Although many studies have demonstrated that neuronal responses are modulated by attention, the significance of this modulation for behavior is poorly understood. We recorded from neurons in the middle temporal (MT) and ventral intraparietal (VIP) areas in the visual cortex of two macaque monkeys while they performed a motion detection task under two conditions of spatial attention. The ability of the animals to detect the motion was reduced when they withdrew attention from the stimulus. Withdrawing attention also reduced neuronal responses to the motion in both the MT and VIP areas. To compare the neuronal and behavioral effects of attention, the amount of attentional modulation was expressed in units of stimulus strength. On average, attention modulated neuronal responses in MT less than needed to account for the attentional effect on behavior. The opposite was observed in VIP, where the average effect of attention on neuronal responses was greater than that needed to account for behavior. Similar results were obtained when the effects of attention on neuronal response and behavioral performance were compared using a parametric function of stimulus strength. Across neurons in both areas, attentional modulation of neuronal responses was more variable than, and uncorrelated with, attentional modulation of behavioral performance. These findings suggest that attention can alter the average relationship between neuronal activity in visual cortex and behavioral performance. Where this relationship is preserved may indicate which cortical regions are most closely associated with the behavior in a given task.

Animals↗
PubMed2005

[The effects of overnight sleep deprivation on cardiovascular autonomic modulation].

OBJECTIVE: This study aimed to delineate cardiovascular autonomic modulation associated with overnight total sleep deprivation (TSD) in humans. METHODS: Cardiovascular autonomic modulation during overnight total sleep deprivation was assessed in 18 normal male subjects [age: (26.2 +/- 4.2) years, BMI (23.9 +/- 1.7) kg/m(2)]. ECG and continuous blood pressure from radial artery tonometry were obtained in seated position before TSD (baseline) and after overnight TSD. Spectral analysis of heart rate variability (HRV) and BP variability (BPV) were computed for cardiac parasympathetic modulation (high frequency power, HF); sympathetic modulation (low frequency power, LF), sympatho-vagal balance (LF/HF power of R-R variability, LF/HF) and BPV sympathetic modulation (low frequency power, BPV LF) in normalized (N) units [(total power of the components)/(total power-very low frequency power) x 100]. RESULTS: No significant changes were found in BP and heart rate. HRV LF was increased significantly from baseline (59.4 +/- 15.7)% to overnight SD (67.0 +/- 13.9)%. HRV LF/HF was increased significantly from baseline (2.7 +/- 1.7) to overnight SD (3.8 +/- 2.3), HRV HFN was decreased from baseline (29.0 +/- 11.6)% to overnight SD (22.8 +/- 10.4)%, BPV LF was significantly increased from baseline (63.2 +/- 16.5)% to overnight SD (72.4 +/- 13.2)%. CONCLUSION: Acute SD was associated with increased sympathetic and decreased parasympathetic cardiovascular modulation.

Adolescent↗
PubMed2005

[Module structure and growth pattern of Stipa baicalansis clone in Songnen Plain of China].

By the method of digging up whole tiller tuft, this paper quantitatively analyzed the module structure and growth pattern of Stipa baicalansis clone under the cultural conditions in the Songnen Plain of Northeast China. The results showed that after two growth seasons of vegetative reproduction, the tuft size of the clone in its growth stopping period at the end of September was 9.4 +/- 3.24 cm, and the total number of the clonal modules was 161.5 +/- 85.2, among which, the individuals of reproductive and vegetative tillers were 14.6 +/- 11.48 and 146.9 +/- 78.70, occupying 9.25% and 90.75% of the total, respectively. The total biomass of the clonal modules was 53.8 +/- 34.22 g, and the biomass of reproductive and vegetative tillers was 25.0 +/- 20.34 g and 28.8 +/- 19.43 g, occupying 43.75% and 56.25% of the total, respectively. With the increase of tuft size, the number of different modules was in a linear isogony growth, while their biomass was in an power allometry growth. There was a significant (P < 0.05) or very significant (P < 0.01) power positive correlation between the biomass of different modules and the number and total biomass of clonal modules. The mean productivity of unit reproductive tiller was about ten times higher than that of unit vegetative tiller, and the phenotype plasticity of the number and biomass of reproductive tiller was larger than that of vegetative tiller.

Biomass↗
PubMed1991

FMRFamide modulation of secretory machinery underlying presynaptic inhibition of synaptic transmission requires a pertussis toxin-sensitive G-protein.

The neuropeptide FMRFamide modulates synaptic transmission between identified neurons of the pond snail Helisoma trivolvis. FMRFamide causes a presynaptic inhibition of transmitter release by actions on ion channels and secretory machinery (Man-Son-Hing et al., 1989). The actions of FMRFamide on secretory machinery were studied using giant synapses that form between somata in culture. Using the calcium cage DM-nitrophen, synchronized, calcium-clamped release of neurotransmitter was promoted by UV photolysis. A series of UV flashes (15 msec duration) repeatedly promoted the transient synchronized release of neurotransmitter. Addition of FMRFamide reduced the magnitude of these flash-evoked inhibitory postsynaptic currents. Under conditions of synchronized transmitter release, FMRFamide modulates the secretory responsiveness to internal calcium. The release of neurotransmitter at somasoma synapses was determined to be quantal in nature. To test for the involvement of G-proteins in mediating the effects of FMRFamide on secretory machinery, the modulation of the frequency of miniature inhibitory postsynaptic currents (MIPSCs) was examined. Addition of FMRFamide reduced the frequency of MIPSCs without affecting intracellular free calcium measured with fura-2. Injection of a nonhydrolyzable analog of GTP, GTP gamma S, mimicked the effect of FMRFamide and reduced MIPSC frequency. Preinjection of the presynaptic soma with the A-protomer of pertussis toxin (PTX) prevented FMRFamide from reducing MIPSC frequency. Thus, a PTX-sensitive G-protein mediates the action of FMRFamide on secretory machinery. Similarly, preinjection of the presynaptic soma with PTX prevented FMRFamide from reducing the magnitude of action potential-evoked IPSC. Dose-response curves for the actions of FMRFamide on secretory machinery and calcium current were constructed and demonstrated that secretory machinery can be modulated at concentrations of FMRFamide (less than or equal to 10(-7) M) that do not affect calcium current magnitude. At a concentration of 10(-7) M FMRFamide, action potential-evoked synaptic transmission was reduced. Thus, synaptic transmission can be regulated by the modulation of secretory machinery, without a requirement for the modulation of ion channels.

Animals↗
PubMed1991

Post-transcriptional and transcriptional control of collagen gene expression in normal and modulated rabbit corneal endothelial cells.

In a previous report, collagen synthesis did not correlate with steady-state collagen RNA levels; substantial amounts of type I collagen RNAs in endothelial cells were not translated into the respective protein. The current investigation was extended to study the level of the control mechanism in collagen gene expression in normal corneal endothelial cells or those modulated by corneal endothelium modulation factor released by polymorphonuclear leukocytes. Northern-blot analysis using cloned rabbit types I and IV cDNA probes (same species as RNA sources) demonstrated specific mRNA transcripts for collagen types I and IV in the endothelial cells, although the steady-state level of these mRNAs in modulated endothelial cells was low. The turnover rate of collagen RNAs was determined; normal cells contain very stable alpha 2(I) and alpha 2(IV) mRNAs whose half-lives exceed 24 hr. The same messages decayed rapidly in the modulated cells, where they had an apparent half-life of approximately 8 hr. Using nuclear run-off transcription, the rate of transcription in normal cells was found to be slightly lower than that in modulated cells. When the relative rate of collagen gene transcription was compared, that of alpha 2(I) was the lowest and of alpha 2(IV), the highest in both cells. The relative transcriptional rates of individual collagen chains did not account for the steady-state levels, suggesting that transcriptional regulation in corneal endothelial cells was less than was translational regulation. On the other hand, during early stages of corneal endothelial cell modulation induced by factors released by polymorphonuclear leukocytes there was a differential effect on both transcriptional rate and the steady-state level of collagen RNAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Phorbol myristate acetate-induced down-modulation of CD4 is dependent on calmodulin and intracellular calcium.

PMA causes rapid down-modulation of CD4 molecules on murine immature thymocytes, human PBL, and CD4-positive human tumor cell lines, but not on murine peripheral lymphocytes. The mechanisms of phorbol ester-induced down modulation of CD4 molecules, however, have not been elucidated. To determine how PMA down-modulates CD4 expression by T lymphocytes, we studied the ability of inhibitors of protein kinase C, calmodulin, actin, and tubulin to block PMA-induced modulation of CD4 in several murine and human cell types. We also tested the ability of intracellular and extracellular calcium chelators to block CD4 internalization. There was marked variability in the degree of PMA-induced down-modulation of CD4 among various cell types. The effects of PMA on CD4 expression were greater for murine thymocytes, for human PBL, and for the human lymphoblastic leukemia cell line, MOLT-3, than for any of the other cell types studied. The protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, blocked phosphorylation but not internalization of CD4 molecules induced by PMA. Therefore, phosphorylation of CD4 molecules by protein kinase C is not required for the internalization of the molecules. Internalization was blocked by both inhibitors of calmodulin, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide, and trifluoperazine. PMA-induced internalization of CD4 was blocked by Quin-2 AM, which chelates intracellular calcium. EGTA, which chelates extracellular calcium, did not block internalization. Inhibitors of actin or tubulin did not block internalization. These results suggest that PMA-induced modulation of CD4 can occur in the absence of phosphorylation of the CD4 molecules and is calmodulin and intracellular calcium dependent.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗