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PubMed1995

Heart beat modulation of spontaneous otoacoustic emissions in guinea pig.

It has been reported that background variation in the frequency of spontaneous otoacoustic emission (SOAEs) may arise from the cardiovascular system and that the side-bands in the spectra of SOAEs may be modulated by heartbeat. For better understanding of the mechanical influence of the cardiac cycle on cochlear functions under physiological and pathophysiological conditions, this study investigated heartbeat-induced modulation of SOAEs in guinea pig. Possible mechanisms of these phenomena are also discussed. The external ear canal acoustic signal, round window electric signal, and the ECG were recorded for off-line analysis from five pigmented guinea pigs with SOAEs. Time and frequency domain averages with synchronization of the heartbeat indicate that both the external ear canal acoustic and round window electric signal contain some component contributed by ECG and phonocardiography. High resolution FFT spectra suggest that SOAEs were modulated by heartbeat and respiration. Theoretically the change in the SOAEs could be from frequency modulation or a combination of frequency and amplitude modulations. Results of a heartbeat-synchronized average of a wave analyzer output at SOAE frequency indicates that amplitude modulation of SOAE does occur. Data obtained in the current experiment support the hypothesis that the heartbeat-related modulation of SOAE in guinea pig is a combination of frequency and amplitude modulation. The proposed mechanism is that pulsatile cochlear blood flow may cause oscillations in cochlear pressure and affect cochlear performance, resulting in heartbeat modulation of SOAEs.

Animals↗
PubMed1985

Temporal modulation transfer functions in normal-hearing and hearing-impaired listeners.

Modulation thresholds for sinusoidally amplitude-modulated broadband noise were obtained from normal-hearing and sensorineural hearing-impaired listeners as a function of modulation frequency. The resulting temporal modulation transfer functions (TMTFs) indicated that the impaired listeners were generally less sensitive than the normals to amplitude modulation and, unlike previously published data from normal-hearing listeners, TMTFs in the impaired listeners were level dependent: sensitivity to modulation, particularly for modulation frequencies greater than 100 Hz, decreased with decreases in level. TMTFs were also obtained with band-limited noise from the normal-hearing listeners: the noise was low-pass filtered at 1.6 kHz after modulation and was generally presented with a 1.6-kHz high-pass masker. The TMTFs in the low-pass condition were similar to the TMTFs obtained with broadband noise from the impaired listeners, suggesting that the impaired temporal processing in the hearing-impaired listeners is a result of a narrower effective, 'internal' bandwidth. Increment thresholds for continuous broadband and low-pass noise were obtained in conditions similar to those in which TMTFs were obtained. In general, a similar power-law relationship between modulation threshold and increment threshold was found to exist for both the normal-hearing and the hearing-impaired listeners.

Adult↗
PubMed1998

In vitro efficacy of known P-glycoprotein modulators compared to droloxifene E and Z: studies on a human T-cell leukemia cell line and their resistant variants.

P-glycoprotein(P-gp)- related resistance is one of the major obstacles in treating leukemia patients. Therefore, it is of clinical interest to find new potential modulators and compare their P-gp-modulating efficacy. The present analysis investigated the influence of P-gp modulators, such as verapamil, tamoxifen, droloxifene E, droloxifene Z, SDZ PSC 833 (PSC 833) and dexniguldipine in a leukemic T-cell line (CCRF-CEM) and its P-gp-resistant counterparts (CCRF-CEM/ACT400 and CCRF-CEM/VCR1000). P-gp expression was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. It was characterized as the percentage of P-gp positive cells and also expressed as a D value by using the Kolmogorov Smirnov statistic. The efficacy of P-gp modulators was determined with the rhodamine-123 accumulation test and the MTT test. An in vitro modulator concentration between 0.1 microM and 3 microM was determined, where no genuine antiproliferative effect was apparent. The modulators PSC 833 and dexniguldipine were the significant (p<C0.05) most potent chemosensitizers followed by verapamil, droloxifene Z, tamoxifen and droloxifene E in descending order. In addition to the modulators PSC 833 and dexniguldipine, droloxifene Z should especially be considered as a candidate for future ex vivo and in vivo studies. The main advantage of droloxifene Z could be the low rate of expected side effects. This fact permits the use of high Drol Z dosage in order to achieve a relevant modulating effect in vivo and to use this drug in combination with a further modulator so as to reach maximum efficacy with tolerable side effects.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Flicker ERG responses to stimuli parametrically modulated in color space.

PURPOSE: To develop methods for recording human electroretinogram (ERG) responses to stimuli that modulate different classes of cones in various ratios, to draw inferences about the combination of cone signal in early retinal processing. METHODS: Subjects viewed large-field temporal modulations presented on a computer-controlled color monitor. A flicker photometric paradigm was used to equate the ERG response elicited by interleaved reference and test modulations. Test modulations were chosen to stimulate the L- and M-cones in various ratios. Results were obtained from color-normal subjects, dichromats, and an anomalous trichromat. RESULTS: Reliable signals were obtained from all subjects to both L- and M-cone-isolating modulations and to intermediate modulations. Signals from color-defective subjects were predominantly determined by the modulation seen by only one cone type, whereas signals from color-normal subjects were sensitive to both L- and M-cone modulations. For most color-normal subjects, the recorded signal was a linear function of the contrasts seen by the L- and M-cones. There was individual variability in how strongly each cone type contributed to the overall signal. CONCLUSIONS: It is straightforward to record signals to color modulations presented on a CRT by using the flicker photometric ERG. For most observers, signals from L- and M-cones combine linearly. The relative contribution of the two cone classes varies across observers, probably because of individual differences in the relative numbers of L- and M-cones.

Adult↗
PubMed2003

Modulation of the voltage-dependent anion-selective channel by cytoplasmic proteins from wild type and the channel depleted cells of Saccharomyces cerevisiae.

It is well known that effective exchange of metabolites between mitochondria and the cytoplasm is essential for cell physiology. The key step of the exchange is transport across the mitochondrial outer membrane, which is supported by the voltage-dependent anion-selective channel (VDAC). Therefore, it is clear that the permeability of VDAC must be regulated to adjust its activity to the actual cell needs. VDAC-modulating activities, often referred to as the VDAC modulator, were identified in the intermembrane space of different organism mitochondria but the responsible protein(s) has not been identified as yet. Because the VDAC modulator was reported to act on VDAC of intact mitochondria when added to the cytoplasmic side it has been speculated that a similar modulating activity might be present in the cytoplasm. To check the speculation we used mitochondria of the yeast Saccharomyces cerevisiae as they constitute a perfect model to study VDAC modulation. The mitochondria contain only a single isoform of VDAC and it is possible to obtain viable mutants devoid of the channel (Deltapor1). Moreover, we have recently characterised a VDAC-modulating activity located in the intermembrane space of wild type and Deltapor1 S. cerevisiae mitochondria. Here, we report that the cytoplasm of wild type and Deltapor1 cells of S. cerevisiae contains a VDAC-modulating activity as measured in a reconstituted system and with intact mitochondria. Since quantitative differences were observed between the modulating fractions isolated from wild type and Deltapor1 cells when they were studied with intact wild type mitochondria as well as by protein electrophoresis it might be concluded that VDAC may influence the properties of the involved cytoplasmic proteins. Moreover, the VDAC-modulating activity in the cytoplasm differs distinctly from that reported for the mitochondrial intermembrane space. Nevertheless, both these activities may contribute efficiently to VDAC regulation. Thus, the identification of the proteins is very important.

Biological Transport↗
PubMed2003

Cerebellar climbing fibers modulate simple spikes in Purkinje cells.

Purkinje cells have two action potentials: Climbing fiber responses (CFRs) and simple spikes (SSs). CFRs reflect the discharge of a single climbing fiber at multiple synaptic sites on the proximal dendrite of the Purkinje cell. SSs reflect the summed action of a subset of parallel fiber synapses on Purkinje cell dendritic spines. Because mossy fiber afferents terminate on granule cells, the ascending axons of which bifurcate, giving rise to parallel fibers, the modulation of SSs has been attributed to mossy fiber afferent signals. This inference has never been tested. Conversely, the low discharge frequency of CFRs has led many to conclude that they have a unique and intermittent role in cerebellar signal processing. We examine the relative potency of vestibularly modulated mossy fiber and climbing fiber signals in evoking CFRs and SSs in Purkinje cells of the uvula-nodulus in chloralose-urethane-anesthetized rabbits. Vestibular primary afferents were blocked by unilateral labyrinthectomy (UL). A UL destroys the vestibular primary afferent signal to the ipsilateral uvula-nodulus, while leaving intact the vestibular climbing fiber signal from the contralateral inferior olive. After UL, vestibular stimulation modulated CFRs and SSs in ipsilateral uvula-nodular Purkinje cells, demonstrating that the primary vestibular afferent mossy fiber input to the ipsilateral uvula-nodulus was not necessary for SS modulation. Unilateral microlesions of the caudal half of the beta-nucleus of the inferior olive reduced a modulated climbing fiber signal to the contralateral uvula-nodulus, causing loss of both vestibularly modulated CFRs and SSs in contralateral Purkinje cells. Vestibular climbing fibers not only evoke low-frequency CFRs, but also indirectly modulate higher-frequency SSs. This modulation must be attributed to cerebellar interneurons. Golgi cell inhibition of granule cells may provide the interneuronal mechanism for CFR-induced SS modulation.

Action Potentials↗
PubMed2003

Evolution of interprofessional learning: Dalhousie University's "From Family Violence to Health" module.

At Dalhousie University, interprofessional (IP) learning modules are used to help future health care professionals learn to work together in resolving complex problems. One module, "From Family Violence to Health," features the role of dental professionals. This paper describes the evolution of this module from the year 2000. By February 2003, 1,182 students from 15 health care professions had completed the module. Qualitative evaluation in years 1 and 2 of the program (2000 and 2001) revealed that, before participating in the IP module, many students were able to identify a role for themselves in the recognition of family violence and knew their responsibility to report incidents. However, after participating in the module, they had a greater understanding of the reporting of family violence, a more comprehensive and supportive perspective, increased recognition of how health care professionals could work together and improved awareness of the roles of other professions. In a quantitative evaluation in year 3 (2002), mean student ratings on a scale of 1 to 5 indicated that the IP module was relevant (4.2), increased their understanding of family violence (4.0), and had some impact in promoting IP learning (3.8). As health care delivery becomes more focused on care teams and system thinking, the provision of IP training is expected to increase. The Dalhousie University IP modules (available at http://www.dal.ca/~fhp/ipl/index.html) address health and social problems for which it is critical that health care and other professionals work together. Feedback from practitioners on the development of IP education is welcomed, particularly with regard to the IP module addressing family violence.

Domestic Violence↗
PubMed1991

Modulation of alkylating agents by etanidazole and Fluosol-DA/carbogen in the FSaIIC fibrosarcoma and EMT6 mammary carcinoma.

Tumor cell survival assay in the FSaIIC murine fibrosarcoma demonstrated that when the modulator Fluosol-DA (0.3 ml; 12 ml/kg i.v.) was administered just prior to an alkylating agent plus carbogen breathing for 6 h or the modulator etanidazole (1 g/kg i.p.) was administered just prior to an alkylating agent, the combination treatment produced significantly more tumor cell killing across the dosage range of each alkylating agent tested compared with the alkylating agent alone. Each alkylating agent produced a dose-dependent log-linear tumor cell survival curve. There was an increase in tumor cell killing of 5-10-fold when either Fluosol-DA/carbogen or etanidazole was added to treatment with the alkylating agent. For cis-diamminedichloroplatinum(II) (CDDP) and N,N',N''-triethylenethiophosphoramide, the modulators used in combination increased tumor cell killing by only 2-3-fold over that obtained with a single modulator, but for the other alkylating agents, tumor cell killing was increased by 10-50-fold when the combination of modulators was used. Bone marrow granulocyte-macrophage colony-forming unit survival assays showed that the combination of modulators with the alkylating agents resulted in only small increases in bone marrow toxicity of the alkylating agents except for N,N',N''-triethylenethiophosphoramide and L-phenylalanine mustard (L-PAM), for which the toxicity to the bone marrow granulocyte-macrophage colony-forming unit was increased by 5-10-fold compared with the alkylating agents alone. The Hoechst 33342 dye diffusion defined tumor cell subpopulation assay, also in the FSaIIC tumor, demonstrated that the combination of modulators increased the toxicity of CDDP, cyclophosphamide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea by 9-55-fold compared with the alkylating agent alone in both the bright (euxoic-enriched) and dim (hypoxic-enriched) cells. For each alkylating agent except 1,3-bis(2-chloroethyl)-1-nitrosourea, the increase in tumor cell killing was greater in the dim cells than in the bright cells. Finally, tumor growth delay studies in both the FSaIIC tumor and the EMT-6 murine mammary adenocarcinoma confirmed that the combination of modulators significantly increased the tumor growth delay caused by CDDP, carboplatin, cyclophosphamide, N,N'N"-triethylenethiophosphoramide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea. The greatest increases (4-5-fold) were observed for carboplatin and L-PAM in the FSaIIC tumor and CDDP and cyclophosphamide in the EMT-6 tumor. These results suggest that Fluosol-DA/carbogen together with etanidazole may be an effective modulator combination of alkylating agents in the clinic.

Alkylating Agents↗
PubMed1991

Evaluation of synthetic novel ether aminophosphoglycerides for glucocorticoid-receptor complex modulator activity.

Modulator is an endogenous low-mol wt regulator of the glucocorticoid-receptor complex. Structural analysis of purified modulator suggested that it was a novel ether aminophosphoglyceride (Bodine and Litwack 1988b). Analogs of the putative modulator structure have now been synthesized. The synthetic compounds are 1-O-(6-carboxylhexyl)-glycero-3-phosphoserine and the sn-2-methoxy and sn-1-ethylester derivatives. Like modulator, these novel synthetic compounds are water soluble. However, thin-layer chromatography and spectroscopic analysis of these phosphoglycerides indicated significant structural differences between modulator and the synthetic analogs. In particular, the chromatographic behavior of the compounds suggests that modulator is more highly charged than the synthetic derivatives. The synthetic compounds, as well as lysophosphatidylserine, were also tested for in vitro modulator activity using the glucocorticoid-receptor complex activation inhibition and steroid-binding stabilization assays. None of the analogs exhibited modulator activity in these assays. However, the synthetic compounds were generally less detrimental to receptor steroid-binding than lysophosphatidylserine. From this work, we conclude that although modulator is not mimicked by one of these synthetic phosphoglycerides, a starting point for future structure-function studies has nonetheless been established.

Amines↗
PubMed1990

Cell surface modulation of CD26 by anti-1F7 monoclonal antibody. Analysis of surface expression and human T cell activation.

In this paper, we examined in detail the ability of anti-1F7 to modulate 1F7 (CD26) surface expression as well as analyzed the functional relationship between the surface expression of CD3, CD2, and CD26 and human T cell activation. We showed that anti-1F7-induced modulation is an energy-dependent process that occurs via capping and internalization of the Ag-antibody complex. Although the recovery rate for Ag reexpression of 1F7 following optimal modulation is relatively delayed, reexpression of 1F7 is greatly accelerated following phorbol ester treatment. Most importantly, we demonstrated that modulation of the CD26 Ag leads to an enhancement in the proliferative activity of modulated human T cells treated with anti-CD3 or anti-CD2, which is preceded by an enhancement in Ca2+ mobilization. CD26 modulation also led to an increase in anti-CD3- or anti-CD2-mediated T cell clone proliferation. Finally, whereas modulation of the CD26 Ag has an effect on CD3- or CD2-induced T cell activation, modulation of the CD3/TCR complex inhibits the proliferative response of T cells incubated with anti-CD3 plus anti-1F7 or anti-CD2 plus anti-1F7. However, modulation of the CD2 structure does not affect anti-CD3- plus anti-1F7-induced human T cell activation. The above results thus provide additional evidence that the CD26 Ag plays an integral role in the regulation of human T cell activation.

Antibodies, Monoclonal↗
PubMed1989

Modulation of human lymphocyte O6-alkylguanine-DNA alkyltransferase by streptozotocin in vivo.

The ability to modulate DNA repair has been proposed as an effective method to overcome cytotoxic drug resistance in human tumors. However, no studies have shown that it is possible to achieve modulation of DNA repair in humans in vivo. This study analyzes modulation of O6-alkylguanine-DNA alkyltransferase, a DNA repair protein that protects cells from cytotoxic DNA adducts formed by nitrosoureas. Streptozotocin has been shown to inactivate the alkyltransferase in vitro and sensitize tumor cells to other nitrosoureas. Thus, we determined whether biochemical modulation of alkyltransferase activity could be documented in patients receiving therapeutic doses of streptozotocin and whether the modulation was specific to streptozotocin or occurred in patients undergoing treatment with other DNA-damaging agents as well. Normal peripheral blood lymphocytes were used to analyze modulation of the alkyltransferase. We found that lymphocyte alkyltransferase activity was significantly decreased 20 h after treatment with streptozotocin (500 mg/m2) or high dose 1,3-bis-(2-chloroethyl)-1-nitrosourea (350 mg/m2) but not after treatment with the other DNA-damaging agents or lower doses of 1,3-bis-(2-chloroethyl)-1-nitrosourea. A cumulative decline in lymphocyte alkyltransferase activity occurred with daily streptozotocin treatment, reaching 26 +/- 9% of control after the third day of treatment (P less than 0.0005). Thus, the alkyltransferase DNA repair protein can be modulated in vivo in humans given systemic drug treatment. While further studies are needed to document that biochemical modulation can be achieved in the target tumor in humans, this study supports the development of clinical trials using streptozotocin as a biochemical modulator of nitrosourea resistance in human malignancies.

Carmustine↗
PubMed1986

The role of frequency modulation in the perception of complex stimuli by primates.

Frequency modulation is a common feature of acoustic communication signals, including both human speech and many animal calls. In this study, linear frequency upsweeps were used as simple abstractions of the modulations found in communication signals. Macaque monkeys were trained using positive reinforcement operant conditioning procedures to respond when an ongoing repetitive acoustic signal changed from unmodulated (pure tone) to modulated (sweep). Thresholds for detecting modulation were determined using the psychophysical method of constant stimuli. In the first experiment, it was shown that the monkeys were most sensitive to modulation around a center frequency of 500 Hz. Subsequent experiments were carried out at that frequency, and varied stimulus duration and the frequency relationship between standard and comparison stimuli. The results of these studies indicated that subjects were responding primarily to discrete frequency cues rather than to the presence of modulation. When a premium was placed on attending to modulation by presenting discrete shifts between successive unmodulated stimuli thereby making such shifts an unreliable indicator of the presence of modulation, subjects continued to respond to the presence of the discrete shifts. These results are taken as evidence that the auditory system may deal with frequency modulation near threshold by recoding it as a discrete frequency percept.

Animal Communication↗
PubMed1985

[Responses of auditory neurons of the medulla oblongata of the frog to presentation of tones with sinusoidal amplitude modulation].

The responses of single units in the medullary auditory regions of the frog Rana ridibunda to sinusoidally amplitude-modulated tones of characteristic frequencies were studied. The reproduction of the sound modulation in the discharge frequency of the units was determined from cycle histograms of the discharges locked to the modulation period. In dorsal nucleus units the amplitude modulation was preserved in the discharge modulation over a wide modulation frequency and sound intensity ranges. In many superior olivary neurons an enhancement of small amplitude changes within the range of modulation frequencies 70-150 Hz was observed. The reaction phase was linear-dependent on the modulation frequency. The best enhancement of amplitude changes took place for small modulation indices.

Animals↗
PubMed1995

Modulator inhibits nuclear translocation of the glucocorticoid receptor and inhibits glucocorticoid-induced apoptosis in the human leukemic cell line CEM C-7.

Modulator is an endogenous low-molecular-weight regulator of both glucocorticoid and mineralocorticoid receptors as well as protein kinase C. Structural analysis of modulator purified to apparent homogeneity suggests that it is a novel ether aminophosphoglyceride. In this report, we show that modulator inhibits cytosolic human glucocorticoid receptor (GR) complex activation as measured by DNA-cellulose binding. In addition, modulator blocks glucocorticoid-induced nuclear translocation of the GR in intact human leukemic (CEM C-7) cells, as illustrated by immunocytochemical localization. Furthermore, we demonstrate that modulator, by blocking the activation and subsequent translocation of GR, inhibits glucocorticoid-mediated apoptosis, characterized by chromatin condensation, internucleosomal DNA fragmentation, and cell death in glucocorticoid-sensitive CEM C-7 cells. Modulator inhibits glucocorticoid-induced c-myc gene repression and glucocorticoid receptor gene up-regulation. These data suggest that modulator functions to regulate the GR in intact cells as well as in cytosolic preparations. In addition, the inhibition of glucocorticoid-induced programmed cell death by modulator sheds light on the cellular function of modulator as well as on the mechanism by which apoptosis occurs in CEM C-7 cells.

Amino Acid Sequence↗
PubMed1993

Phosphorylation/dephosphorylation of the receiver module at the conserved aspartate residue controls transphosphorylation activity of histidine kinase in sensor protein ArcB of Escherichia coli.

A membrane sensor protein, ArcB, recognizes anaerobic environments and signals the information to the cognate regulator, ArcA. This in vitro study presents the process and control of the signal-transduction phosphorylation. In the presence of ATP, the ArcB transmitter module undergoes autophosphorylation and then transfers the phosphoryl group to its own receiver module as well as to the ArcA receiver module. Results suggest that the phosphoryl group of the ArcB receiver module is released by an intrinsic phosphatase activity. D-Lactate inhibits the phosphatase activity that removes phosphoaspartate groups from the receiver module in ArcB, and the associated increase in phosphorylation of this module leads to an activation of transphosphorylation of subsequently added phosphohistidine groups on ArcB to the receiver module of ArcA. A similar effect was also observed in the presence of pyruvate, acetate, or NADH. Conversely, the non-phosphorylated ArcB receiver module completely inhibits the intermolecular transphosphorylation. Thus, the phosphorylation state of the ArcB receiver module controls signal transduction from ArcB to ArcA. Since the intrinsic phosphatase activity is inhibited by cellular metabolites that increasingly accumulate by anaerobiosis, the enzyme portion of ArcB may be involved in sensing anaerobic environments through cellular metabolites in vivo.

Amino Acid Sequence↗
PubMed1998

Putative multiadhesive protein from the marine sponge Geodia cydonium: cloning of the cDNA encoding a fibronectin-, an SRCR-, and a complement control protein module.

Sponges (Porifera) representing the simplest metazoan phylum so far have been thought to possess no basal lamina tissue structures. One major extracellular matrix protein that is also a constitutive glycoprotein of the basal lamina is fibronectin. It was the aim of the present study to identify the native protein from the marine sponge Geodia cydonium and to isolate the corresponding cDNA. In crude extracts from this sponge protein(s) of M(r) of approximately 230 and approximately 210 kDa could be visualized by Western-blotting using an anti-fibronectin [human] antibody. By PCR cloning from a cDNA library of G. cydonium we isolated a cDNA comprising one element of fibronectin, the type-III (FN3) module. The cDNA (2.3 kb long), encoding a 701 amino acid [aa] long putative "multiadhesive protein" termed MAP_GEOCY, was found to contain (i) a fibronectin-, (ii) a scavenger receptor cysteine-rich [SRCR]-, and (iii) a short consensus repeat [SCR] module. The 89 aa long fibronectin module comprises the characteristic topology and conserved aa found in fibronectin type-III (FN3) elements. The SRCR module (101 aa) features the characteristics of group B SRCR molecules. The predominant proteins belonging to this group are the mammalian WC1-, M130-, CD6- and CD5 antigens that probably are involved in immunological reactions. The SCR module (54 aa) shows the characteristics of type III SCR modules found in complement receptors. Phylogenetic analyses performed with all three building blocks of the "multiadhesive protein" showed that the respective sponge modules form independent, possibly basal, lineages in trees that include the corresponding modules from higher metazoan animals. In summary, these data demonstrate for the first time that the phylogenetically oldest Metazoa, the sponges, contain protein modules seen in higher animals in proteins of the extracellular matrix and in molecules involved in cell-mediated immune reactions in vertebrates.

Amino Acid Sequence↗
PubMed1998

Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro.

A tetrodotoxin-resistant voltage-gated Na+ current (TTX-R INa) appears to be the current primarily responsible for action potential generation in the cell body and terminals of nociceptive afferents. Although other voltage-gated Na+ currents are modulated by the activation of protein kinase C (PKC), protein kinase A (PKA), or both, the second messenger pathways involved in the modulation of TTX-R INa are still being defined. We have examined the modulation of TTX-R INa in isolated sensory neurons with whole-cell voltage-clamp recording. Activation of either PKC or PKA increased TTX-R INa. PKA activation also produced a leftward shift in the conductance-voltage relationship of TTX-R INa and an increase in the rates of current activation, deactivation, and inactivation. Inhibitors of PKC decreased TTX-R INa, whereas inhibitors of PKA had no effect on the current. Investigating the interaction between PKC and PKA revealed that although inhibitors of PKA had little effect on PKC-induced modulation of TTX-R INa, inhibitors of PKC significantly attenuated PKA-induced modulation of the current. Finally, although PGE2-induced modulation of TTX-R INa was more similar to PKA-induced modulation of the current than to PKC-induced modulation, PGE2-induced effects were inhibited by inhibitors of both PKC and PKA. Thus, although TTX-R INa is a common target for cellular processes involving the activation of either PKA or PKC, PKC activity is necessary to enable subsequent PKA-mediated modulation of TTX-R INa.

Animals↗
PubMed1998

Absence of cyclic adenosine 3':5' monophosphate responsive element modulator expression at the spermatocyte arrest stage.

OBJECTIVE: To test the hypotheses that variations in the expression of adenosine 3':5' monophosphate (cAMP) responsive element modulator are found in human seminiferous epithelium in men with impaired testicular function and subsequent infertility and that variations in apoptosis frequency are associated with differential cAMP responsive element modulator expression in male infertility states. DESIGN: Standard immunohistochemical staining using a rabbit polyclonal antibody against the tau isoform of the cAMP responsive element modulator protein was performed on 5-microM sections of Bouin's fixed, paraffin-embedded testicular tissue obtained from azoospermic or severely oligozoospermic men for routine clinical purposes. Histologic diagnosis was confirmed with computerized image analysis of Feulgen-stained sections. SETTING: Tertiary male infertility referral center at a medical school. PATIENT(S): Forty-eight testis biopsies were performed in 38 azoospermic or severely oligozoospermic males. INTERVENTION(S): Rabbit polyclonal cAMP responsive element modulator tau antibody was applied to the paraffin-embedded testis sections. MAIN OUTCOME MEASURE(S): Testis immunoreactivity to polyclonal cAMP responsive element modulator tau antibody and apoptotic indices. RESULT(S): Although cAMP responsive element modulator immunoreactivity was present in the round spermatid stage of meiosis in testis biopsy specimens showing normal spermatogenesis, spermatid maturation arrest, and hypospermatogenesis, there was complete absence of expression in biopsy specimens from patients with Sertoli cell only and spermatocyte maturation arrest states. In addition, significantly increased apoptotic indices were observed in the spermatocyte maturation arrest state in comparison with normal spermatogenesis and Sertoli cell only pattern. CONCLUSION(S): These data suggest that cAMP responsive element modulator may be important for spermatid development and a stage-specific regulator of human spermatogenesis. Absence of cAMP responsive element modulator may be a cause of testicular failure in various types of male infertility.

Adult↗