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PubMed2005

Specific modulation of airway epithelial tight junctions by apical application of an occludin peptide.

Tight junctions are directly involved in regulating the passage of ions and macromolecules (gate functions) in epithelial and endothelial cells. The modulation of these gate functions to transiently regulate the paracellular permeability of large solutes and ions could increase the delivery of pharmacological agents or gene transfer vectors. To reduce the inflammatory responses caused by tight junction-regulating agents, alternative strategies directly targeting specific tight junction proteins could prove to be less toxic to airway epithelia. The apical delivery of peptides corresponding to the first extracellular loop of occludin to transiently modulate apical paracellular flux has been demonstrated in intestinal epithelia. We hypothesized that apical application of these occludin peptides could similarly modulate tight junction permeability in airway epithelia. Thus, we investigated the effects of apically applied occludin peptide on the paracellular permeability of molecular tracers and viral vectors in well differentiated human airway epithelial cells. The effects of occludin peptide on cellular toxicity, tight junction protein expression and localization, and membrane integrity were also assessed. Our data showed that apically applied occludin peptide significantly reduced transepithelial resistance in airway epithelia and altered tight junction permeability in a concentration-dependent manner. These alterations enhanced the paracellular flux of dextrans as well as gene transfer vectors. The occludin peptide redistributed occludin but did not alter the expression or distribution of ZO-1, claudin-1, or claudin-4. These data suggest that specific targeting of occludin could be a better-suited alternative strategy for tight junction modulation in airway epithelial cells compared with current agents that modulate tight junctions.

Amino Acid Sequence↗
PubMed2006

Characterization of nicotinic acetylcholine receptors that modulate nicotine-evoked [3H]norepinephrine release from mouse hippocampal synaptosomes.

Nicotine's modulation of hippocampal noradrenergic neurotransmission may contribute to its mnemonic properties, but the nicotinic acetylcholine receptor (nAChR) subtypes that modulate terminal release of norepinephrine are unknown. In the present study, we used a number of subtype-selective alpha-conotoxins in combination with nicotinic receptor subunit-deficient mice to characterize nAChRs that modulate [3H]nore-pinephrine release from synaptosomes. The results indicate that at least two populations of nAChRs contribute to this release: a novel alpha6(alpha4)beta2beta3beta4 subtype and an alpha6(alpha4)beta2beta3 subtype. These are distinct from subtypes that modulate synaptosomal norepinephrine release in the rat hippocampus in which an alpha6/beta2 and/or alpha6/beta4 ligand binding interface is not present. Whereas alpha-conotoxin MII fully inhibits nicotine-evoked [3H]norepinephrine release in mouse, it is ineffective in blocking [3H]norepinephrine release in rat. Block of [3H]norepinephrine release by alpha-conotoxin BuIA, a toxin that kinetically distinguishes between beta2- and beta4-containing nAChRs, was partially reversible in mouse but irreversible in rat. This indicates that in contrast to rat, mouse nAChRs are made of both beta4 and non-beta4-containing populations. Results from beta2 and beta4 null mutant mice confirmed this conclusion, indicating the presence of the beta2 subunit in all nAChRs and the presence of the beta4 subunit in a subpopulation of nAChRs. In addition, both alpha4 and beta3 subunits are essential for the formation of functional nAChRs on mouse noradrenergic terminals. Cytisine, a ligand formerly believed to be beta4-selective, was a highly effective agonist for alpha6beta2-containing nAChRs. The sum of these results suggests a possible novel nAChR subtype that modulates nor-adrenergic neurotransmission within the mouse hippocampus.

Alkaloids↗
PubMed1997

Characterization of a novel bisacridone and comparison with PSC 833 as a potent and poorly reversible modulator of P-glycoprotein.

Novel compounds, composed of two acridone moieties connected by a propyl or butyl spacer, were synthesized and tested as potential modulators of P-glycoprotein (P-gp)-mediated multidrug resistance. The propyl derivative 1,3-bis(9-oxoacridin-10-yl)-propane (PBA) was extremely potent and, at a concentration of 1 microM, increased steady state accumulation of vinblastine (VLB) approximately 9-fold in the multidrug-resistant cell line KB8-5. In contrast to the readily reversible effects of VRP and cyclosporin A on VLB uptake and similar to the effects of the cyclosporin analog PSC 833, this modulation by PBA was not fully reversed 6-8 hr after transfer of cells to PBA-free medium. Continuous exposure to 3 microM PBA was nontoxic and could completely reverse VLB resistance in KB8-5 cells. Consistent with its effects on VLB transport, the drug resistance-modulating effect of PSC 833 was significantly more persistent than that of VRP. However, the effect of PBA was, like that of VRP, rapidly reversed once the modulator was removed from the extracellular environment. PBA was able to compete with radiolabeled azidopine for binding to P-gp and to stimulate P-gp ATPase activity. However, both the steady state accumulation of PBA and the rate of efflux of PBA were similar in drug-sensitive KB3-1 and drug-resistant KB8-5 cells, suggesting that this compound is not efficiently transported by P-gp. These results indicate that PBA represents a new class of potent and poorly reversible synthetic modulators of P-gp-mediated VLB transport.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

P2Y receptors modulate ion channel function through interactions involving the C-terminal domain.

Nucleotide stimulation of G(q)-coupled P2Y receptors expressed in Xenopus laevis oocytes produces the activation of an endogenous voltage-gated ion channel, previously identified as the transient inward (T(in)) channel. Expression of human P2Y(1), human P2Y(2), rat P2Y(6), human P2Y(11), or skate P2Y receptors in oocytes resulted in modulation of the voltage dependence and inactivation gating of the channel. Expression of the human P2Y(4) receptor, rat M(1)-muscarinic receptor, and human B(1)-bradykinin receptor did not alter the properties of the T(in) channel. Replacement of the C-terminal domain of the human B(1)-bradykinin receptor with the C-terminal domains of either the human P2Y(1) or human P2Y(2) receptor resulted in voltage dependence and inactivation-gating properties, respectively, of the T(in) channel that were similar to those elicited by the respective native P2Y receptor. Systematic truncation of the C-terminal region of the human P2Y(1) receptor identified a short region responsible for modulation of the T(in) channel. This region contains a conserved sequence motif found in all P2Y receptors that modulates the voltage dependence of the T(in) channel. Synthetic 20-mer peptides from the C-terminal domains of human P2Y(1) and P2Y(2) receptors produced a shift in the voltage dependence and slowed inactivation gating, respectively, after injection into oocytes expressing human B(1)-bradykinin or truncated human P2Y(1) receptors. These results indicate that certain P2Y receptors are capable of modulating the voltage sensitivity and inactivation gating of an endogenous oocyte ion channel through interactions involving the C-terminal region of the receptor. Such modulation of ion channel function could also exist in native mammalian cells that express P2Y receptors.

Amino Acid Sequence↗
PubMed1988

Two trans-acting regulatory genes (vir and mod) control antigenic modulation in Bordetella pertussis.

Expression of virulence factors by Bordetella pertussis is altered by environmental signals (antigenic modulation) and is dependent on an activator encoded by a gene called vir. We have used TnphoA (Tn5 IS50L::phoA) gene fusions to define two sets of genes whose expression is either activated (vag loci) or repressed (vrg loci) by modulation signals. Both groups of genes appear to be regulated by the vir gene product in that, in the absence of modulators, null mutations in vir lead to the repression of vag gene fusions and derepression of vrg gene fusions. Mutants of B. pertussis were isolated that constitutively express virulence factors in the presence of the modulator MgSO4, nicotinic acid, or low incubation temperature. We designate the gene that carries such mutations mod (modulation) and have characterized one (mod-1) of these mod constitutive mutations. A method was developed for the insertional inactivation of the vir gene by using the integration of a suicide replicon. Inactivation of the vir gene in the mod-1 mutant, followed by transcomplementation with the cloned wild-type vir gene, gives the Mod-1 constitutive phenotype, showing that the mod-1 mutation defines a gene distinct from vir. The gene carrying the mod-1 mutation is linked to vir and was cloned on a recombinant cosmid (pLAF-C1) which transcomplements the vir-1::Tn5 mutation in B. pertussis 347. Introduction of pLAF-C1 into vir mutant and vir+ B. pertussis strains also gives the Mod-1 constitutive phenotype, indicating that mod-1 is a dominant allele. These data suggest that the mod gene product could have sensory functions for the environmental signals that affect the expression of vir-regulated genes of B. pertussis. The mod constitutive strains and plasmids described here also have applications in pertussis vaccine development.

Bordetella pertussis↗
PubMed1989

Pertussis toxin promoter sequences involved in modulation.

Previous analysis of the pertussis toxin (PT) promoter has shown that expression of PT requires a trans-activating factor encoded by the vir locus and a 170-base-pair DNA sequence upstream from the transcription start site containing a 21-base-pair direct repeat sequence crucial trans-activation (R. Gross and R. Rappuoli, Proc. Natl. Acad. Sci. USA 85:3913-3917, 1988). In this paper we extend the analysis to the modulative response to environmental stimuli. We show that modulation acts at the transcriptional level and occurs only in phase I bacteria. Modulation also requires a functional vir locus and the same promoter region of 170 base pairs. We show that, in addition to the previously identified direct repeat, even the sequences downstream from position -117 are required for trans-activation and modulation and that the deletion of four cytosine residues at position -31 causes the inactivation of the promoter. The kinetics of the change in transcription show that the PT promoter can be shut off very rapidly by adding 50 mM MgSO4 to the medium, whereas resumption of transcription after removal of the modulative agents from the medium is slow.

Base Composition↗
PubMed1997

Effect of a modulator deletion on transcription of the human cytomegalovirus major immediate-early genes in infected undifferentiated and differentiated cells.

Differentiation-dependent expression of the human cytomegalovirus (HCMV) major immediate-early (MIE) genes, encoding IE1 and IE2, may partly govern virus replication in monocytic THP-1 and embryonal carcinoma (Tera-2) cells. The modulator of the MIE promoter was shown previously in transient transfection assays to repress transcription from promoter segments in undifferentiated THP-1 and Tera-2 cells but not in differentiated cells. To determine the biological importance of these findings, we constructed a recombinant HCMV (r delta MSVgpt) without a modulator. In comparison to wild-type (WT) virus, r delta MSVgpt exhibits a slight delay in growth in human fibroblasts, but there is no appreciable change in IE1 and IE2 transcription. Moreover, there is no appreciable change in the early/late kinetics of transcription of RNAs colinear with the predicted UL128 coding region, which is adjacent to the modulator, although the size distribution and abundance of these RNAs are altered. In infected undifferentiated THP-1 and Tera-2 cells, WT and r alpha MSVgpt viruses produce minimal but comparable amounts of IE1 RNAs. The genomes of both viruses are detectable in similar amounts within these undifferentiated cells. Induction of cellular differentiation before infection overcomes the block in MIE gene transcription. WT and r alpha MSVgpt infections of differentiated THP-1 cells produce similar levels of IE1 and IE2 RNAs. Thus, differentiation-dependent control of MIE gene transcription involves regulatory mechanisms other than the modulator. Possible alternative functions of the modulator are discussed.

Cell Differentiation↗
PubMed1998

Modulation of viral immunoinflammatory responses with cytokine DNA administered by different routes.

The efficacy of plasmid DNA encoding cytokine administered by different routes, systemic or surface exposure, was evaluated and compared for their modulating effects on subsequent lesions caused by infection with herpes simplex virus (HSV). Systemic or topical administration of both interleukin-4 (IL-4) and IL-10 DNA but not IL-2 DNA caused a long-lasting suppression of HSV-specific delayed-type hypersensitivity response. IL-4 or IL-10 DNA preadministration also modulated the expression of immunoinflammatory lesions associated with corneal infection of HSV. Suppression of ocular lesions required that the DNA be administered to the nasal mucosa or ocular surfaces and was not evident after intramuscular administration. The modulating effect of IL-10 DNA was most evident after topical ocular administration, whereas the effects of IL-4 DNA given by both routes appeared to be equal. Preexposure of IL-4 DNA, but not IL-10 DNA, resulted in a significant change in Th subset balance following HSV infection. Our results indicate that the modulating effect of IL-4 or IL-10 DNA may proceed by different mechanisms. Furthermore, our results suggest that surface administration of cytokine DNA is a convenient means of modulating immunoinflammatory lesions.

Animals↗
PubMed2004

Lentiviral vectors interfering with virus-induced CD4 down-modulation potently block human immunodeficiency virus type 1 replication in primary lymphocytes.

CD4 down-modulation is essential for the production of human immunodeficiency virus (HIV) infectious particles. Disease progression correlates with enhanced viral induced CD4 down-modulation, and a subset of long-term nonprogressors carry viruses defective in this function. Despite multiple pieces of evidence highlighting the importance of this function in viral pathogenesis in vivo, to date, HIV-induced CD4 down-modulation has not been used as a target for intervention. We describe here HIV-based vectors that deliver truncated CD4 molecules resistant to down-modulation by the viral products Nef and Vpu. Infection of cells previously transduced with these vectors proceeded normally, and viral particles were released in normal amounts. However, the infectivity of the released virions was reduced 1,000-fold. Lentiviral vectors expressing truncated CD4 molecules were efficient at blocking HIV-1 infectivity and replication in several cell lines and in CD4-positive primary lymphocytes. The findings presented here provide proof-of-principle that approaches targeting the virus-induced CD4 down-modulation may constitute the basis for novel anti-HIV therapies.

CD4 Antigens↗
PubMed1994

Mutational analysis of the transcription activation domain of RelA: identification of a highly synergistic minimal acidic activation module.

The potent C-terminal activation domain of the RelA (p65) subunit of the cellular transcription factor NF-kappa B is shown to contain several discrete acidic activation modules. These short, approximately 11-amino-acid modules were able to give rise to only a low level of transcription activation when fused to the GAL4 DNA-binding domain as monomers. However, dimers and higher-order multimers activated the transcription of minimal promoter elements as effectively as the full-length RelA or VP16 activation domain. Therefore, this 11-amino-acid RelA-derived acidic module appears to contain all of the sequence information required to fully activate a target promoter element as long as it is presented in a form that permits functional synergy. Critical primary sequence requirements for acidic activation module function included a core phenylalanine residue and flanking bulky hydrophobic residues. Overall negative charge was necessary but not sufficient for function. While dimeric forms of the 11-amino-acid acidic activation module bound to either TFIIB or TATA-binding protein efficiently in vitro, a similarly charged peptide lacking the core phenylalanine residue failed to interact. Overall, these data demonstrate that the biological activity of the RelA activation domain is dependent on acidic activator sequences that are closely comparable to those detected in the activation domain of the viral VP16 regulatory protein. We hypothesize that the ability of these acidic activators to specifically interact with multiple components of the transcription initiation complex likely underlies the dramatic functional synergy exhibited by this class of activation domains in vivo.

Amino Acid Sequence↗
PubMed2005

A mannanase, ManA, of the polycentric anaerobic fungus Orpinomyces sp. strain PC-2 has carbohydrate binding and docking modules.

The anaerobic fungus Orpinomyces sp. strain PC-2 produces a broad spectrum of glycoside hydrolases, most of which are components of a high molecular mass cellulosomal complex. Here we report about a cDNA (manA) having 1924 bp isolated from the fungus and found to encode a polypeptide of 579 amino acid residues. Analysis of the deduced sequence revealed that it had a mannanase catalytic module, a family 1 carbohydrate-binding module, and a noncatalytic docking module. The catalytic module was homologous to aerobic fungal mannanases belonging to family 5 glycoside hydrolases, but unrelated to the previously isolated mannanases (family 26) of the anaerobic fungus Piromyces. No mannanase activity could be detected in Escherichia coli harboring a manA-containing plasmid. The manA was expressed in Saccharomyces cerevisiae and ManA was secreted into the culture medium in multiple forms. The purified extracellular heterologous mannanase hydrolyzed several types of mannan but lacked activity against cellulose, chitin, or beta-glucan. The enzyme had high specific activity toward locust bean mannan and an extremely broad pH profile. It was stable for several hours at 50 degrees C, but was rapidly inactivated at 60 degrees C. The carbohydrate-binding module of the Man A produced separately in E. coli bound preferably to insoluble lignocellulosic substrates, suggesting that it might play an important role in the complex enzyme system of the fungus for lignocellulose degradation.

Aerobiosis↗
PubMed1985

Verification and evaluation of internal flow and motion. True magnetic resonance imaging by the phase gradient modulation method.

We report qualitative and quantitative evaluation and verification studies of the bipolar phase gradient modulation method for true MR imaging of internal flow and motion velocities. Velocity encoding modulations provide speed-of-motion and direction-sensitive images using special phase-sensitive reconstructions. True motion MR imaging does not depend upon subject parameters, T1 or T2, nor upon selective active-volume time-of-flight calculations, nor is it limited strictly to fluid-flow velocities. Conventional MR sequences often induce strong accidental phase gradient modulations that can cause severe artifacts in conventional MR scans and limit the useful sensitivities of true motion MR. Multiple steps of velocity encoding allow resolution of separate elements of the velocity spectrum, and enable suppression of all such phase-artifact difficulties. Some view-to-view phase inconsistencies are intrinsic to the subject being scanned, e.g., strong motion variations during the heart cycle; limitations due to such effects require external modifications in the scanning, such as cardiac gating. Since conventional density information remains in the data, independent of velocity encoding modulations, we suggest a multiple encoding sequence and saving the MR raw data. These evaluations and verifications demonstrate exciting potential in clinical application for the phase gradient modulation method of true flow and motion MR imaging.

Biophysical Phenomena↗
PubMed2005

Modulation of tyramine signaling by osmolality in an insect secretory epithelium.

The control of water balance in multicellular organisms depends on absorptive and secretory processes across epithelia. This study concerns the effects of osmolality on the function of the Malpighian tubules (MTs), a major component of the insect excretory system. Previous work has shown that the biogenic amine tyramine increases transepithelial chloride conductance and urine secretion in Drosophila MTs. This study demonstrates that the response of MTs to tyramine, as measured by the depolarization of the transepithelial potential (TEP), is modulated by the osmolality of the surrounding medium. An increase in osmolality caused decreased tyramine sensitivity, whereas a decrease in osmolality resulted in increased tyramine sensitivity; changes in osmolality of +/-20% resulted in a nearly 10-fold modulation of the response to 10 nM tyramine. The activity of another diuretic agent, leucokinin, was similarly sensitive to osmolality, suggesting that the modulation occurs downstream of the tyramine receptor. In response to continuous tyramine signaling, as likely occurs in vivo, the TEP oscillates, and an increase in osmolality lengthened the period of these oscillations. Increased osmolality also caused a decrease in the rate of urine production; this decrease was attenuated by the tyraminergic antagonist yohimbine. A model is proposed in which this modulation of tyramine signaling enhances the conservation of body water during dehydration stress. The modulation of ligand signaling is a novel effect of osmolality and may be a widespread mechanism through which epithelia respond to changes in their environment.

Animals↗
PubMed1983

Local modulation of intestinal ion transport by enteric neurons.

Principles of autonomic nervous system control of intestinal ion transport need to include the newer concepts of the enteric nervous system (ENS). Based on studies of nervous control of the myenteric plexus, it is likely that ENS control of intestinal transport occurs through local mechanisms. In vitro transport studies and a limited number of radioreceptor-binding studies in mucosal cells support the notion that putative neurotransmitters alter transport by acting directly with mucosal receptors. In vivo and in vitro studies cannot alone uncover the indirect transport effects that neurotransmitters may have when they interact with enteric neurons. Studies focused on uptake and release of neurotransmitters suggest that norepinephrine (NE)-induced absorption may be modulated by local NE presynaptic neuronal mechanisms. Endogenous NE release may be enhanced by nicotinic and angiotensin II agents but decreased by muscarinic and alpha-adrenergic agents or prostaglandins. Presynaptic neuronal mechanisms that modulate endogenous acetylcholine (ACh) release and ACh-induced secretion are less well defined. Intestinal transport may be controlled by negative feedback, interneuronal, or transsynaptic presynaptic mechanisms. We propose that transport is controlled by a balance between the principal neurotransmitters NE and ACh. These neurotransmitters may be modulated by neuroactive peptides located either in neurons or in enteroendocrine cells. Efferent neurons may modulate release of neuropeptides from enteroendocrine cells into the luminal or antiluminal sides of mucosal cells. Intestinal transport also may be controlled by luminal factors that cause neuropeptide release from enteroendocrine cells or by specialized luminal receptors acting on sensory afferent neurons and intrinsic neuronal reflexes. Therefore, local modulation of intestinal transport by the ENS represents a finely tuned neuronal system with complex interrelations similar to many found in the central nervous system.

Animals↗
PubMed2001

Modulation of alpha-ENaC and alpha1-Na+-K+-ATPase by cAMP and dexamethasone in alveolar epithelial cells.

cAMP and dexamethasone are known to modulate Na+ transport in epithelial cells. We investigated whether dibutyryl cAMP (DBcAMP) and dexamethasone modulate the mRNA expression of two key elements of the Na+ transport system in isolated rat alveolar epithelial cells: alpha-, beta-, and gamma-subunits of the epithelial Na+ channel (ENaC) and the alpha1- and beta1-subunits of Na+-K+-ATPase. The cells were treated for up to 48 h with DBcAMP or dexamethasone to assess their long-term impact on the steady-state level of ENaC and Na+-K+-ATPase mRNA. DBcAMP induced a twofold transient increase of alpha-ENaC and alpha1-Na+-K+-ATPase mRNA that peaked after 8 h of treatment. It also upregulated beta- and gamma-ENaC mRNA but not beta1-Na+-K+-ATPase mRNA. Dexamethasone augmented alpha-ENaC mRNA expression 4.4-fold in cells treated for 24 h and also upregulated beta- and gamma-ENaC mRNA. There was a 1.6-fold increase at 8 h of beta1-Na+-K+-ATPase mRNA but no significant modulation of alpha1-Na+-K+-ATPase mRNA expression. Because DBcAMP and dexamethasone did not increase the stability of alpha-ENaC mRNA, we cloned 3.2 kb of the 5' sequences flanking the mouse alpha-ENaC gene to study the impact of DBcAMP and dexamethasone on alpha-ENaC promoter activity. The promoter was able to drive basal expression of the chloramphenicol acetyltransferase (CAT) reporter gene in A549 cells. Dexamethasone increased the activity of the promoter by a factor of 5.9. To complete the study, the physiological effects of DBcAMP and dexamethasone were investigated by measuring transepithelial current in treated and control cells. DBcAMP and dexamethasone modulated transepithelial current with a time course reminiscent of the profile observed for alpha-ENaC mRNA expression. DBcAMP had a greater impact on transepithelial current (2.5-fold increase at 8 h) than dexamethasone (1.8-fold increase at 24 h). These results suggest that modulation of alpha-ENaC and Na+-K+-ATPase gene expression is one of the mechanisms that regulates Na+ transport in alveolar epithelial cells.

Animals↗
PubMed1995

Epithelial modulation of afferent nerve endings: differential effects of amiloride on afferent subtypes.

Mechanisms underlying the differing chemosensitivity of laryngeal afferents have not been defined. The role of airway epithelium in transducing the chemical stimuli to neural signals was investigated by using Na(+)- and Cl(-)-channel inhibitors in anesthetized spontaneously breathing cats. Single-fiber action potentials were recorded from the peripheral cut end of the superior laryngeal nerve. Luminal application of amiloride (10(-4) M), an inhibitor of epithelial Na+ channels, reduced the responsiveness of non-respiratory-modulated endings (n = 25) to distilled water (65.76 +/- 5.77 vs. 50.67 +/- 5.13 Hz; P < 0.01). Water responsiveness of these endings was unaffected by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and diphenylamine-2-carboxylate, two Cl(-)-channel blockers. Respiratory-modulated endings (water responsive, n = 8; water nonresponsive, n = 9) were unaffected by Na(+)- and Cl(-)-channel blockers. These results suggest that epithelial Na+ channels play a role in the modulation of non-respiratory-modulated laryngeal endings. The lack of an effect by amiloride on other subtypes may be due to differences in location or intrinsic properties of nerve endings. Cl- channels do not appear to play an important role in the modulation of laryngeal afferents targeted in this study.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2006

Nitric oxide in B6 mouse and nitric oxide-sensitive soluble guanylate cyclase in cat modulate acetylcholine release in pontine reticular formation.

ACh regulates arousal, and the present study was designed to provide insight into the neurochemical mechanisms modulating ACh release in the pontine reticular formation. Nitric oxide (NO)-releasing beads microinjected into the pontine reticular formation of C57BL/6J (B6) mice significantly (P < 0.0001) increased ACh release. Microdialysis delivery of the NO donor N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine (NOC-12) to the mouse pontine reticular formation also caused a concentration-dependent increase in ACh release (P < 0.001). These are the first neurochemical data showing that ACh release in the pontine reticular formation of the B6 mouse is modulated by NO. The signal transduction cascade through which NO modulates ACh release in the pontine reticular formation has not previously been characterized. Therefore, an additional series of studies quantified the effects of a soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), on ACh release in the cat medial pontine reticular formation. During naturally occurring states of sleep and wakefulness, but not anesthesia, ODQ caused a significant (P < 0.001) decrease in ACh release. These results show for the first time that NO modulates ACh in the medial pontine reticular formation of the cat via an NO-sensitive sGC signal transduction cascade. Isoflurane and halothane anesthesia have been shown to decrease ACh release in the medial pontine reticular formation. The finding that ODQ did not alter ACh release during isoflurane or halothane anesthesia demonstrates that these anesthetics disrupt the NO-sensitive sGC-cGMP pathway. Considered together, results from the mouse and cat indicate that NO modulates ACh release in arousal-promoting regions of the pontine reticular formation via an NO-sensitive sGC-cGMP pathway.

Acetylcholine↗
PubMed2003

Neural control of rhythmic human arm movement: phase dependence and task modulation of hoffmann reflexes in forearm muscles.

Although we move our arms rhythmically during walking, running, and swimming, we know little about the neural control of such movements. Our working hypothesis is that neural mechanisms controlling rhythmic movements are similar in the human lumbar and cervical spinal cord. Thus reflex modulation during rhythmic arm movement should be similar to that seen during leg movement. Our main experimental hypotheses were that the amplitude of H-reflexes in the forearm muscles would be modulated during arm movement (i.e., phase-dependent) and would be inhibited during cycling compared with static contraction (i.e., task-dependent). Furthermore, to determine the locus of any modulation, we tested the effect that active and passive movement of the ipsilateral (relative to stimulated arm) and contralateral arm had on H-reflex amplitude. Subjects performed rhythmic arm cycling on a custom-made hydraulic ergometer in which the two arms could be constrained to move together (180 degrees out of phase) or could rotate independently. Position of the stimulated limb in the movement cycle is described with respect to the clock face. H-reflexes were evoked at 12, 3, 6, and 9 o'clock positions during static contraction as well as during rhythmic arm movements. Reflex amplitudes were compared between tasks at equal M wave amplitudes and similar levels of electromyographic (EMG) activity in the target muscle. Surface EMG recordings were obtained bilaterally from flexor carpi radialis as well as from other muscles controlling the wrist, elbow, and shoulder. Compared with reflexes evoked during static contractions, movement of the stimulated limb attenuated H-reflexes by 50.8% (P < 0.005), 65.3% (P < 0.001), and 52.6% (P < 0.001) for bilateral, active ipsilateral, and passive ipsilateral movements, respectively. In contrast, movement of the contralateral limb did not significantly alter H-reflex amplitude. H-reflexes were also modulated by limb position (P < 0.005). Thus task- and phase-dependent modulation were observed in the arm as previously demonstrated in the leg. The data support the hypothesis that neural mechanisms regulating reflex pathways in the moving limb are similar in the human upper and lower limbs. However, the inhibition of H-reflex amplitude induced by contralateral leg movement is absent in the arms. This may reflect the greater extent to which the arms can be used independently.

Adult↗