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Results for “clonal modeling”

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PubMed1996

Membrane depolarization in PC-12 cells during hypoxia is regulated by an O2-sensitive K+ current.

The effects of hypoxia on K+ current (IK), resting membrane potential, and cytosolic free Ca2+ in rat pheochromocytoma (PC-12) cells were studied. Whole cell voltage- and current-clamp experiments were performed to measure IK and membrane potential, respectively. Cytosolic free Ca2+ level was measured using the Ca(2+)-sensitive fluorescent dye fura 2. Depolarizing voltage steps to +50 mV from a holding potential of -90 mV elicited a slowly inactivating, tetraethylammonium chloride-sensitive, and Ca(2+)-insensitive IK that was reversibly inhibited by reduced O2 tension. Graded reduction in PO2 (from 150 to 0 mmHg) induced a graded inhibition of O2-sensitive IK [IK(O2)] up to 46% at 0 mmHg. Moreover, hypoxia induced a 19-mV membrane depolarization and a twofold increase in cytosolic free Ca2+. In Ca(2+)-free condition, inhibition of IK(O2) induced an 8-mV depolarization, suggesting that inhibition of IK(O2) was responsible for initiating depolarization. The effect of reduced PO2 on the current-voltage relationship showed a reduction of outward current and a 14-mV shift in the reversal potential comparable with the amount of depolarization measured in current clamp experiments. Neither Ca(2+)-activated IK nor inwardly rectifying IK are responsible for the hypoxia-induced depolarization. In conclusion, PC-12 cells express an IK(O2), inhibition of which leads to membrane depolarization and increased intracellular Ca2+, making the PC-12 clonal cell line a useful model for studying the molecular and biophysical mechanisms that mediate O2 chemosensitivity.

Animals↗

PubMed1985

Analysis of cell surface light chain immunoglobulin expression by flow cytometry in normal controls: a new mathematical approach.

It has been observed in flow cytometric studies that in normal individuals there are proportionally more kappa+ than lambda+ bearing light chain B-cells. Overt predominance of one type of light chain bearing cell over the other is a characteristic of B-cell neoplasias, a phenomenon called clonal excess (CE). A mathematical model using the Weibull distribution is proposed for studying such an excess. The new approach is desirable for two reasons: First, it is parametric and hence offers a more sensitive and versatile analysis than its nonparametric counterparts. Second, it utilizes only the relevant information from the upper tails of the distributions of the fluorescence intensity of the kappa+ and lambda+ cells. Two measures of CE based on the Weibull model are proposed, and a normal range of variability was determined for each measure using a random sample of 48 normal controls. Such normal ranges are particularly useful in detecting cancer patients with minimal B-cell neoplasias. A comparative study of the new measures, Ault's maximum difference measure, and a measure based on Ligler's method showed that the parametric approach provides much more sensitivity than both the nonparametric ones.

B-Lymphocytes↗

PubMed2006

Coordinate regulation of neuropeptide Y and agouti-related peptide gene expression by estrogen depends on the ratio of estrogen receptor (ER) alpha to ERbeta in clonal hypothalamic neurons.

Neuropeptide Y (NPY) and agouti-related peptide (AgRP) stimulate feeding, whereas NPY also facilitates the estrogen-mediated preovulatory GnRH surge. In addition to regulating reproductive function, estrogen also acts as an anorexigenic hormone, although it is not yet known which hypothalamic neurons are involved in this process. We hypothesize that estrogen may directly control hypothalamic NPY and/or AgRP synthesis to influence energy homeostasis. Using two clonal, murine hypothalamic neuronal cell models, N-38 and N-42, we demonstrate that 17beta-estradiol differentially regulates estrogen receptor (ER)alpha and ERbeta levels, as well as NPY and AgRP gene expression in a manner that is temporally coordinated with the changes in ER abundance. The estrogen-mediated repression of NPY and AgRP mRNA levels in N-38 and N-42 neurons require either ERalpha and ERbeta or ERalpha alone, respectively, whereas the induction of NPY and AgRP in N-38 neurons is strictly ERbeta dependent, as assessed by ER-specific agonists and small interfering RNA knockdown of ERalpha or ERbeta. Through transient transfection analysis in N-38 neurons, we have mapped the estrogen-mediated repression of NPY to within -1078 of the 5' regulatory region of the NPY gene. Our results provide the first evidence that NPY and AgRP gene expression is directly regulated by estrogen in specific hypothalamic neurons, and that this regulation is dependent upon the ratio of ERbeta to ERalpha. The biphasic control of neuronal NPY/AgRP transcription may be a mechanism by which estrogen has distinct effects on both energy homeostasis and reproduction.

Agouti-Related Protein↗

PubMed2026

Mechanism-Driven Diagnostic Development: A Specimen-Aware Framework Illustrated by Colorectal Cancer and Solid Tumours.

Translational oncology has moved rapidly from histopathology and single-analyte biomarkers toward multi-dimensional molecular profiling. Yet many clinically deployed tests still use reductionist biomarker strategies that under-represent cancer complexity. This review examines whether a mechanistic, multi-layered, and specimen-aware approach can improve cancer detection, classification, prognosis, minimal residual disease (MRD) assessment, and therapeutic selection. Evidence across solid tumours shows that genomic alterations alone incompletely explain tumour state, metastatic behaviour, immune evasion, or therapeutic vulnerability. Integrated genome and transcriptome analyses, proteogenomics, single-cell atlases, fragmentomic, methylation based cell-free DNA assays, metabolomics and microbiome assessments reveal clinically relevant biology that single modality tests cannot determine. Minimally invasive collected specimens can extend access to screening, diagnosis and longitudinal monitoring, but the choice of specimen should be matched to disease biology and analytes that represent mechanisms of oncogenesis. However, translation remains constrained by pre-analytical variability, contamination, differences in tumour shedding behaviour, clonal haematopoiesis, translation of generated models, incomplete external validation and uncertain downstream clinical utility for emerging platforms. This review provides a commentary on the future of cancer diagnostics, the considerations and barriers to clinical translation, the relationship between utility and dimensionality of biomarkers assessed and the emerging rationale towards mechanistically grounded integrated models.

biomarkers↗

PubMed2002

CD40 signaling in B cells regulates the expression of the Pim-1 kinase via the NF-kappa B pathway.

The ability of CD40 signaling to regulate B cell growth, survival, differentiation, and Ig class switching involves many changes in gene expression. Using cDNA expression arrays and Northern blotting, we found that CD40 signaling increased the mRNA levels for pim-1, a protooncogene that encodes a serine/threonine protein kinase. Subsequent experiments showed that CD40 engagement also increased both Pim-1 protein levels and Pim-1 kinase activity in B cells. We then investigated the signaling pathways by which CD40 regulates Pim-1 expression and found that CD40 up-regulates Pim-1 primarily via the activation of NF-kappaB. Inhibiting the activation of NF-kappaB, either by treating cells with a chemical inhibitor, BAY11-7082, or by inducibly expressing a superrepressor form of IkappaBalpha, significantly impaired the ability of CD40 to increase Pim-1 protein levels. Because Pim-1 expression is associated with cell proliferation and survival, we asked whether this correlated with the ability of CD40 signaling to prevent anti-IgM-induced growth arrest in the WEHI-231 murine B cell line, a model for Ag-induced clonal deletion. We found that the anti-IgM-induced growth arrest in WEHI-231 cells correlated with a substantial decrease in Pim-1 levels. In contrast, culturing WEHI-231 cells with either anti-CD40 Abs or with the B cell mitogen LPS, both of which prevent the anti-IgM-induced growth arrest, also prevented the rapid decline in Pim-1 levels. This suggests that Pim-1 could regulate the survival and proliferation of B cells.

Animals↗

PubMed2002

Chromosomal alterations during metastasis formation of head and neck squamous cell carcinoma.

Comparative genomic hybridization (CGH) was used to detect chromosomal changes during metastasis formation of head and neck squamous cell carcinomas (HNSCCs). In total, 92 tumors of 54 patients were investigated. In 34 of these, the metastases were compared to the corresponding primary tumors. The group of metastatic tumors was also compared with 20 nonmetastatic tumors. Gain of 3q was the earliest genetic marker for invasion and metastasis and also correlated with poor prognosis. Additional metastasis-associated lesions were gains on 11q13, 7q11.2, 1q21-q22, and losses on 8p, 11p14, 11q14-qter, 10p12, 10q, and 14q. The incidence of the chromosomal changes was used to evaluate their significance and temporal order of appearance during tumor dissemination, thus leading to an extended progression model of HNSCC. In the clonality analysis, three different methods revealed a mean concordance of 64 and 68% between pairs of primaries and metastases, respectively. Using different similarity scores, the correct metastasis was identified from the pool of all metastatic lesions in 19-26 of the 34 cases. The study supplements previous genetic results on HNSCC pathogenesis and provides criteria for multiple tumor analysis.

Carcinoma, Squamous Cell↗

PubMed1985

Phenotypic variation in clonal Abelson virus lymphoma cells.

Two clonal A-MuLV lymphoma cell lines have the capacity to generate phenotypic variants when grown in vivo as ascites tumors. Variant lines differed from parental lymphoma cells in their expression of enzymatic or cell surface differentiation markers. Parental lines expressed the B220 and Lyb-2 glycoproteins characteristic of pre-B cells and bound B220-specific monoclonal antibodies such as 14.8. The parental cells expressed low levels of TdT activity but did not synthesize detectable mu-heavy chain, a cellular phenotype that may correspond to lymphoid progenitor cells. Three classes of phenotypic variants were recovered from the Thy-1- parental lines: 1) 14.8+, Lyt-1+, Thy-1- cells; 2) 14.8 +/-, Lyt-1+, Thy-1+ cells, and 3) 14.8-, Lyt-1+, Thy-1+ cells. Cell cloning experiments indicated that Thy-1+ variant cells can be recovered within 14 days of in vivo inoculation as a minor proportion (1/10(6] of the tumor cell population and subsequently become the predominant tumor cell population. These clonal tumor lines provide a model for the study of cellular and molecular alterations that occur during neoplastic differentiation and progression in the lymphoid system.

Abelson murine leukemia virus↗

PubMed1994

Volatile anesthetic-induced efflux of calcium from IP3-gated stores in clonal (GH3) pituitary cells.

BACKGROUND: Many hormones and neurotransmitters produce their effects by stimulating the generation of inositol 1,4,5-trisphosphate (IP3), a chemical second messenger that releases Ca2+ from intracellular stores. Interruption of this pathway is a potential mechanism through which volatile anesthetics might inhibit chemically mediated communication between cells. This study used GH3 cells (a clonal cell line) as a model system in which to characterize the effects of volatile anesthetics on IP3-induced mobilization of Ca2+ from intracellular stores. METHODS: Intracellular Ca2+ concentration ([Ca2+]i) was continuously monitored in suspensions of GH3 cells at 37 degrees C using the fluorescent Ca2+ indicator Fura-2. Thyrotropin releasing hormone (TRH) was used to discharge IP3-sensitive intracellular Ca2+ stores. The effects of halothane, isoflurane, and octanol on TRH-induced Ca2+ mobilization were assessed as a function of time and anesthetic concentration. To distinguish between anesthetic effects on Ca2+ uptake and Ca2+ release, experiments were performed using thapsigargin (a Ca(2+)-ATPase inhibitor) to inhibit Ca2+ uptake into IP3-sensitive stores. RESULTS: Halothane increased resting [Ca2+]i and caused a time- and concentration-dependent inhibition of TRH-induced increases in [Ca2+]i (IC50 = 0.6 mM). Thapsigargin, in concentrations that completely inhibit Ca2+ uptake by IP3-sensitive stores, also caused a time-dependent reduction in the [Ca2+]i response to TRH; the time constant of this decay describes the rate of spontaneous leak of Ca2+ from IP3-sensitive stores (tau = 98 +/- 9 s). In the presence of thapsigargin, halothane produced concentration-dependent increases in the rate of leak from IP3-sensitive stores (tau = 74 +/- 12 and 46 +/- 6 s at 0.5 and 1.0 mM halothane, respectively). Isoflurane and octanol also produced concentration-dependent inhibition of the [Ca2+]i response to TRH. CONCLUSIONS: Halothane causes a concentration-dependent leak of Ca2+ from IP3-sensitive stores, leading to depletion of the stores and inhibition of IP3-induced increases in [Ca2+]i. This effect occurs at clinically relevant concentrations of halothane (as well as isoflurane and octanol) and may be an important mechanism underlying some of the physiologic effects of volatile anesthetics.

Anesthetics↗

PubMedDate not supplied

Desensitization of the antigen receptor primes B cells for activation by superstimulatory influenza virus.

Interaction of the B cell receptor (BCR) with non-immunogenic receptor ligands can induce a specific state of B cell unresponsiveness as a result of receptor desensitization. Provided it is maintained over time, BCR desensitization may provide the molecular basis for clonal anergy. Using an in vitro model of anti-Ig-mediated BCR desensitization, we assessed the susceptibility of desensitized "anergic" B lymphocytes to activation by B cell superstimulatory influenza virus hemagglutinin (HA). Rabbit anti-mouse Ig antibodies (whole Ig molecule or F(ab')(2)-fragments) totally abolished the response of murine B cells to HA, when added simultaneously with the virus. Pretreatment with the same antibodies, however, yielding a complete unresponsiveness to a subsequent challenge with normally mitogenic anti-Ig reagents, even enhanced the subsequent proliferative response to HA. By contrast, HA-mediated high-rate immunoglobulin synthesis was suppressed after desensitization. BCR-desensitized, HA-stimulated B cells exhibited a hyperexpression of various activation markers (B7, major histocompatibility complex class II, CD25) and served as potent antigen-presenting cells (APC) in a polyclonal model for T lymphocyte activation. These observations suggest a possible scenario for the breaking of natural B cell tolerance, where infections with B cell superstimulatory viruses may lead to the clonal expansion of receptor desensitized, functionally silenced B lymphocytes in vivo.

Animals↗

PubMed1997

The epithelial cell-specific integrin, CD103 (alpha E integrin), defines a novel subset of alloreactive CD8+ CTL.

The interaction of CD8+CTL with epithelial layers is an important but poorly defined aspect of organ allograft rejection. We herein report that CD103 (formerly alpha E integrin), a known receptor for the epithelial cell-specific ligand E-cadherin, is expressed by a major subset of CD8 + CTL elicited in response to allogeneic renal epithelial cells (REC). In contrast, CD103 was expressed poorly on CD8 + CTL generated in the conventional manner by stimulation with allogeneic leukocytes, although expression could be dramatically up-regulated by supplementing cultures with REC or exogenous TGF-beta 1. That TGF-beta controls the expression of CD103 on CD8+ CTL was further supported by the capacity of anti-TGF-beta mAb to block the generation of such cells in anti-REC cultures. Clonal analyses of anti-REC cultures revealed that individual CD8+ CTL clones were discretely CD103+ or CD103-, nd maintained their respective phenotypes independently of the cell type used for clonal restimulation. In a mouse model of graft-vs-host disease, 16.4 +/- 2.7% of CD8 cells that infiltrated host kidneys were CD103+ (n = 4). CD8 kidney-infiltrating lymphocytes were predominantly of donor origin and displayed an activated/memory phenotype (CD62L-, CD44high), consistent with expression of CD103 on a CD8 effector subset elicited in vivo following allogeneic transplantation. Taken together, the present data demonstrate that CD103 identifies a novel CD8 effector subset and, moreover, that such cells may comprise a significant component of the response to allogeneic tissues. The potential for CD103+ CTL as an important effector mechanism in organ allograft rejection, and more generally, as a mechanistic basis for tissue-specific immune phenomena, is discussed.

Animals↗

PubMedDate not supplied

New mechanisms of viral persistence in primary human immunodeficiency virus (HIV) infection.

Viruses, including the Human Immunodeficiency Virus (HIV), have evolved multiple strategies to overcome host immune defenses, allowing them to persist in the host. Molecular and cellular approaches were simultaneously used to provide sensitive and unbiased delineation of the diversity and dynamics of the immune response, and to study the relative compartimentalization of HIV-specific CTL clones in patients undergoing primary HIV infection. This approach revealed that some HIV-specific CTL clones can be deleted in presence of high levels of antigen, a phenomenon analogous to high-dose tolerance or clonal exhaustion described in murine models of persistent viral infections. Also, HIV-specific CTL clones were found to accumulate preferentially in peripheral blood as compared to lymph nodes, even though the large majority of viral replication during primary HIV infection takes place within lymph nodes. These two mechanisms may decrease the effectiveness of the host cell-mediated immune responses, and favor the establishment of virus persistence during primary HIV infection.

Animals↗

PubMed2025

PhyClone: accurate Bayesian reconstruction of cancer phylogenies from bulk sequencing.

MOTIVATION: Cancer is driven by somatic mutations that result in the expansion of genomically distinct sub-populations of cells called clones. Identifying the clonal composition of tumours and understanding the evolutionary relationships between clones is a crucial task in cancer genomics. Bulk DNA sequencing is commonly used for studying the clonal composition of tumours, but it is challenging to infer the genetic relationship between different clones due to the mixture of different cell populations. RESULTS: In this work, we introduce a new probabilistic model called PhyClone that can infer clonal phylogenies from bulk-sequencing data. We demonstrate the performance of PhyClone on simulated and real-world datasets and show that it outperforms previous methods in terms of accuracy and sample scalability. AVAILABILITY AND IMPLEMENTATION: Source code is available on Github at: https://github.com/Roth-Lab/PhyClone under the GPL v3.0 license.

Neoplasms↗

PubMed2006

Clonal interference and the periodic selection of new beneficial mutations in Escherichia coli.

The conventional model of adaptation in asexual populations implies sequential fixation of new beneficial mutations via rare selective sweeps that purge all variation and preserve the clonal genotype. However, in large populations multiple beneficial mutations may co-occur, causing competition among them, a phenomenon called "clonal interference." Clonal interference is thus expected to lead to longer fixation times and larger fitness effects of mutations that ultimately become fixed, as well as to a genetically more diverse population. Here, we study the significance of clonal interference in populations consisting of mixtures of differently marked wild-type and mutator strains of Escherichia coli that adapt to a minimal-glucose environment for 400 generations. We monitored marker frequencies during evolution and measured the competitive fitness of random clones from each marker state after evolution. The results demonstrate the presence of multiple beneficial mutations in these populations and slower and more erratic invasion of mutants than expected by the conventional model, showing the signature of clonal interference. We found that a consequence of clonal interference is that fitness estimates derived from invasion trajectories were less than half the magnitude of direct estimates from competition experiments, thus revealing fundamental problems with this fitness measure. These results force a reevaluation of the conventional model of periodic selection for asexual microbes.

Cloning, Molecular↗

PubMed1999

The degrees of plasma cell clonality and marrow infiltration adversely influence the prognosis of AL amyloidosis patients.

BACKGROUND AND OBJECTIVE: Primary amyloidosis is a lethal form of plasma cell (PC) dyscrasia characterized by deposits of monoclonal immunoglobulin light chains that cause organ dysfunction. In contrast to multiple myeloma, the amyloid clone is typically indolent and of small size, and marrow PC clonality is not always apparent. This is generally investigated by analyzing the light chain isotype ratio in bone marrow PC. We investigated whether the degree of PC infiltration (PC%) and clonality (PC isotype ratio) affected survival in 56 consecutive patients with primary amyloidosis. DESIGN AND METHODS: PC% was determined by morphologic examination. Immunofluorescence microscopy was used to determine the PC light chain isotype ratio. Statistical analysis was carried out using Cox regression models. RESULTS: The degrees of PC clonality and infiltration were inversely correlated with survival (PC isotype ratio, p = 0.001; PC%, p = 0.008). The two variables were weakly correlated (p = 0.02; r = 0.3). Bone marrow PC isotype ratio demonstrated a powerful independent prognostic value at multivariate analysis when analyzed together with congestive heart failure (the major known negative prognostic factor) and PC%. k/l ratio cut-off values of 0.2 (l patients, p = 0.022) and 16 (k patients, p = 0.03) discriminated two groups with a similar number of patients and significantly different survivals. INTERPRETATION AND CONCLUSIONS: PC clonality and marrow infiltration are important parameters that influence prognosis, presumably because they reflect the amount of pathogenic light chain synthesis.

Adult↗

PubMed1997

Clonality and life cycles of intestinal crypts explained by a state dependent stochastic model of epithelial stem cell organization.

The organization and control of stem cells is a key issue in epithelial cell biology. The small intestinal murine crypt is a useful tissue to study such problems since stem cells are known to be located at specific positions at the bottom of the crypt where they are self maintaining. Recent data suggest, that (1) the number of active stem cells in a crypt can fluctuate, (2) the immediate progeny of a single stem cell can replace other stem cells eventually leading to monoclonality and (3) the life cycle of crypts may be linked to stem cell dynamics. It is the objective of this paper to suggest a stochastic state-dependent model of stem cell and crypt growth which can explain and-link these phenomena into one comprehensive framework. Monte Carlo simulations are performed to show consistently with available data. The model explains the size distribution of small intestinal crypts in steady state, the observations of stem cell fluctuations and monoclonality conversion, recovery of the crypt population after moderate damage and the rate of crypt fission and extinction. The key assumption of this model is an autoregulatory control of stem cell growth.

Animals↗

PubMed2006

Clonal propagation and the fast generation of karyotype diversity: An in vitro Leishmania model.

In the present work we studied the karyotype stability during long-term in vitro maintenance in 3 cloned strains of Leishmania (Viannia) peruviana, Leishmania (Viannia) braziliensis and a hybrid between both species. Only the L. (V.) peruviana strain showed an unstable karyotype, even after subcloning. Four chromosomes were studied in detail, each of them characterized by homologous chromosomes of different size (heteromorphy). Variations in chromosome patterns during in vitro maintenance were rapid and discrete, involving loss of heteromorphy or appearance of additional chromosome size variants. The resulting pattern was not the same according to experimental conditions (subinoculation rate or incubation temperature), and interestingly, this was associated with differences in growth behaviour of the respective parasites. No change in total ploidy of the cells was observed by flow cytometry. We discuss several mechanisms that might account for this variation of chromosome patterns, but we favour the occurrence of aneuploidy, caused by aberrant chromosome segregation during mitosis. Our results provide insight into the generation of karyotype diversity in natural conditions and highlight the relativity of the clone concept in parasitology.

Animals↗

PubMed2001

The population structure of Neisseria meningitidis serogroup A fits the predictions for clonality.

The population structure of Neisseria meningitidis is supposedly epidemic according to. The model predicts that linkage disequilibrium in N. meningitidis populations is only temporary and arises due to the outgrowth of highly successful clonal genotypes from an essentially sexual population. These clones should disappear after a few years because of frequent recombination. In contrast, multilocus enzyme electrophoresis (MLEE) data had previously been interpreted as showing that serogroup A meningococci are truly clonal and possess only limited genetic variability (Wang et al., 1992). The two interpretations are contradictory. In order to elucidate the true population structure of serogroup A meningococci, we analyzed data for a representative group of 84 serogroup A isolates obtained by MLEE, random amplified polymorphic DNA (RAPD) and multilocus sequence typing (MLST). Analysis of linkage disequilibrium and bootstrap analyses of cluster analysis showed a strongly structured population with highly significant linkage disequilibrium. This was not due to the overrepresentation of certain genotypes, in contrast to the expectations for an epidemic population. The analyses identify two main clades, within each of which linkage disequilibrium was also highly significant, thus, excluding a cryptic speciation model. These observations support a population structure based on clonal evolution, in which clones are much more stable than expected for epidemic clonality. We propose that serogroup A meningococci may possess a different population structure from other serogroups of Neisseria meningitidis.

Clone Cells↗

PubMed1996

Interactions between tachykinins and diverse, human nicotinic acetylcholine receptor subtypes.

Nicotinic acetylcholine receptors (nAChR) are diverse members of the ligand-gated ion channel superfamily of neurotransmitter receptors and play critical roles in chemical signaling throughout the nervous system. Reports of effects of substance P (SP) on nAChR function prompted us to investigate interactions between several tachykinins and human nAChR subtypes using clonal cell lines as simple experimental models. Acute exposure to SP inhibits carbamylcholine- or nicotine-stimulated function measured using 86Rb+ efflux assays of human ganglionic (alpha 3 beta 4) nAChR expressed in SH-SY5Y neuroblastoma cells (IC50 approximately 2.3 microM) or of human muscle-type (alpha 1 beta 1 gamma delta) nAChR expressed in TE671/RD clonal cells (IC50 approximately 21 microM). SP also acutely blocks function of rat ganglionic nAChR expressed in PC12 pheochromocytoma cells (IC50 approximately 2.1 microM). Neurokinin A and eledoisin inhibit function (extrapolated IC50 values between 60 and 160 microM) of human muscle-type or ganglionic nAChR, but neurokinin B does not, and neither human nAChR is as sensitive as PC12 cell alpha 3 beta 4-nAChR to eledoisin or neurokinin A inhibition. At concentrations that produce blockade of nAChR function, SP fails to affect binding of [3H]acetylcholine to human muscle-type or ganglionic nAChR. SP-mediated blockade of rat or human ganglionic nAChR function is insurmountable by increasing agonist concentrations. Collectively, these results indicate that tachykinins act noncompetitively to inhibit human nAChR function with potencies that vary across tachykinins and nAChR subtypes. They also indicate that tachykinin actions at nAChR could further contribute to complex cross-talk between nicotinic cholinergic and tachykinin signals in regulation of nervous system activity.

Animals↗