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PubMed1996

[Effects of different natural stimulants on the activity of the rabbits' carotid chemoreceptor].

The effects of different natural stimulants on the afferent unit discharge of rabbit carotid chemoreceptors were studied in the in vitro carotid body- sinus nerve preparation. A total of 32 chemoreceptive units were recorded. The results were as follows: (1) Of the 32 units, 10 (31%) showed chemosensory responses only to PO2 decrease; 9 (28%) to all stimulants (PO2 decrease, PCO2 increase and pH decrease); 9 (28%) to PO2 decrease and PCO2 increase; 3 (9%) to PO2 decrease and pH decrease; only one to pH decrease. (2) The potency of the three natural stimulants in eliciting the changes in intensity of discharge showed a decreasing order as follows: PO2 decrease > PCO2 increase > pH decrease. The above results suggest that the carotid body may contain only one or a combination of 2 or 3 kinds of chemoreceptors respectively sensitive to decrease PO2 to increase PCO2 or decrease pH.

Afferent Pathways↗
PubMed1978

Interaction of peripheral and central respiratory drives in cats. I. Effects of sodium cyanide as a peripheral chemoreceptor stimulus at different levels of CSF pH.

In cats anesthetized with chloralose-urethane, the central respiratory chemoreceptors were exposed to mock CSF of pH 7.02, 7.02, or 7.57. The right carotid body was simultaneously stimulated by intracarotid injections of 40, 80, or 160 microgram sodium cyanide in 200 microliter Ringer solution. The left carotid nerve and, in some animals, both vagosympathetic truncs were dissected. It could be demonstrated that the increase in ventilation produced by application of NaCN to the peripheral chemoreceptors is significantly larger at high than at low mock CSF pH (i.e. at low than at high central stimulus intensity). In vagotomized cats the responses of VT and V to NaCN similarly depend upon CSF pH; they are somewhat larger, though, than in intact animals. These results are discussed as compared with results reported by different authors.

Animals↗
PubMed1994

The prevention of radiosurgery-induced nausea and vomiting by ondansetron: evidence of a direct effect on the central nervous system chemoreceptor trigger zone.

Nausea and emesis are significant side effects in patients undergoing stereotactic radiosurgery for brain lesions in the region of the chemoreceptor trigger zone (area postrema of the brain). Even with the current antiemetic treatment (prochlorperazine +/- corticosteroids), those side effects remain significant. The purpose of this study is twofold: [1] to evaluate the efficacy of ondansetron in inhibiting nausea and emesis in stereotactic radiosurgery patients and [2] to demonstrate that ondansetron's locus of action is the central nervous system (CNS) chemoreceptor trigger zone in the area postrema. In a pilot study, 10 patients receiving > or = 350 cGy in a single fraction of radiosurgery to the region of the area postrema received 32 mg ondansetron iv 1 hour prior to treatment +/- corticosteroids. In a retrospective analysis these results were compared to those of patients with similar features (and matched for radiation dose to the area postrema and the dose of corticosteroids) who received prochlorperazine +/- corticosteroids. Nine of 10 patients in the ondansetron group had no nausea or emesis within 48 hours after treatment; one patient experienced one episode of emesis. In the prochloreperazine group, eight patients had symptoms, three patients needed hospitalization or a physician's care for emesis within 24 hours, and five had nausea with no specific treatment. These preliminary results suggest that ondansetron is a safe and efficient drug to prevent nausea and emesis in this patient group. The precise mechanism of action of ondansetron in these patients is unknown, but is likely due to the drug's serotonin-blocking effect within the CNS. A randomized, prospective study has been started at our institution to confirm these preliminary results.

Adult↗
PubMed1980

Inhibitory and excitatory effects of dopamine on carotid chemoreceptors.

The effect of intravenous dopamine on carotid body chemoreceptor activity was investigated in 6 anesthetized cats which were paralyzed and artificially ventilated. Studies were performed at 4 steady-state PaO2 levels at a constant PaCO2 and at 4 levels of PaCO2 during hyperoxia. Dopamine inhibited carotid chemoreceptors before and excited them after haloperidol. Moderate stimulation of the receptors by hypoxia and hypercapnia augmented dopamine's effects. These results indicate that both inhibitory and excitatory dopamine receptors are present in the carotid body.

Animals↗
PubMed1991

Expression of messenger RNAs for peptides and tyrosine hydroxylase in primary sensory neurons that innervate arterial baroreceptors and chemoreceptors.

Retrograde fiber tracing and in situ hybridization were used to determine expression of mRNAs for preprotachykinin A (ppTA), calcitonin gene related peptide (CGRP), preproenkephalin A (ENK), neuropeptide tyrosine (NPY) and somatostatin (SOM) as well as tyrosine hydroxylase (TH) in the petrosal ganglia primary sensory neurons which innervate carotid sinus baroreceptors and carotid body chemoreceptors. Perfusion of the carotid sinus with the retrogradely transported dye (Fluoro-Gold) labeled primary sensory neurons in petrosal ganglion. Numerous somata in the petrosal ganglion labeled with dye contained mRNAs for all the above peptides, except SOM. Moreover, TH mRNA was found in a substantial number of retrogradely labeled cells in the petrosal ganglion. This study provides information concerning which of the numerous peptides identified in sensory neurons of petrosal ganglion may be involved in modulation of the arterial baroreceptor and chemoreceptor reflexes.

Animals↗
PubMed2001

Voltage-gated K+ channels in chemoreceptor sensory neurons of rat petrosal ganglion.

A subpopulation of sensory neurons in the petrosal ganglion transmits information between peripheral chemoreceptors (glomus cells) in the carotid body and relay neurons in the nucleus of the solitary tract. Expression of voltage-gated K+ channels in these neurons was characterized by immunohistochemical localization. Five members of the Kv1 family, Kv1.1, Kv1.2, Kv1.4, Kv1.5 and Kv1.6 and members of two other families, Kv2.1 and Kv4.3, were identified in over 90% of the chemoreceptor neurons. Although the presence of these channel proteins was consistent throughout the population, individual neurons showed considerable variation in K+ current profiles.

Animals↗
PubMed2002

Inter-receptor communication through arrays of bacterial chemoreceptors.

The sensing mechanisms of chemotactic bacteria allow them to respond sensitively to stimuli. Escherichia coli, for example, respond to changes in chemoattractant concentration of less than 10% over a range spanning six orders of magnitude. Sensitivity over this range depends on a nonlinear relationship between ligand concentration and output response. At low ligand concentrations, substantial amplification of the chemotactic signal is required; however, the mechanism responsible for this amplification remains unclear. Here we demonstrate that inter-receptor communication within a lattice acts to amplify and integrate sensory information. Synthetic multivalent ligands that interact through the low-abundance, galactose-sensing receptor Trg stabilize large clusters of chemoreceptors and markedly enhance signal output from these enforced clusters. On treatment with multivalent ligands, the response to the attractant serine is amplified by at least 100-fold. This amplification requires a full complement of chemoreceptors; deletion of the aspartate (Tar) or dipeptide (Tap) receptors diminishes the amplification of the serine response. These results demonstrate that the entire array is involved in sensing. This mode of information exchange has general implications for the processing of signals by cellular receptors.

Bacterial Proteins↗
PubMed1996

Methylation segments are not required for chemotactic signalling by cytoplasmic fragments of Tsr, the methyl-accepting serine chemoreceptor of Escherichia coli.

The serine chemoreceptor Tsr and other methyl-accepting chemotaxis proteins (MCPs) control the swimming behaviour of Escherichia coli by generating signals that influence the direction of flagellar rotation. MCPs produce clockwise (CW) signals by stimulating the autophosphorylation activity of CheA, a cytoplasmic histidine kinase, and counter-clockwise signals by inhibiting CheA. CheW couples CheA to chemoreceptor control by promoting formation of MCP/CheW/CheA ternary complexes. To identify MCP structural determinants essential for CheA stimulation, we inserted fragments of the tsr coding region into an inducible expression vector and used a swimming contest called 'pseudotaxis' to select for transformant cells carrying CW-signalling plasmids. The shortest active fragment we found, Tsr (350-470), stimulated CheA in a CheW-dependent manner, as full-length Tsr molecules do. It spans a highly conserved 'core' (370-420) that probably specifies the CheA and CheW contact sites and other determinants needed for stimulatory control of CheA. Tsr (350-470) also carries portions of the left and right arms flanking the core, which probably play roles in regulating MCP signalling state. However, this Tsr fragment lacks all of the methylation sites characteristic of MCP molecules, indicating that methylation segments are not essential for generating receptor output signals.

Amino Acid Sequence↗
PubMed2004

Crosslinking snapshots of bacterial chemoreceptor squads.

The team signaling model for bacterial chemoreceptors proposes that receptor dimers of different detection specificities form mixed trimers of dimers. These receptor "squads" then recruit the cytoplasmic signaling proteins CheA and CheW to form ternary signaling teams, which typically cluster at the poles of the cell. We devised cysteine-directed in vivo crosslinking approaches to ask whether mixed receptor squads could form in the absence of CheA and CheW and, if so, whether the underlying structural interactions conformed to trimer-of-dimers geometry. One approach used cysteine reporters at positions in the serine (Tsr) and aspartate (Tar) receptors that should form disulfide-linked Tsr approximately Tar products when juxtaposed at the interface of a mixed trimer. Another approach used a cysteine reporter with trigonal geometry near the trimer contact region and a trifunctional maleimide reagent with a spacer length appropriate for capturing the three axial subunits in a trimer of dimers. Both approaches detected mixed receptor-crosslinking products in cells lacking CheA and CheW. Under these conditions, receptor methylation and ligand-binding state had no discernable effect on crosslinking efficiencies. Crosslinking with the trigonal reporter was rapid and did not increase with longer treatment times or higher reagent concentrations, suggesting that this method produces a short-exposure snapshot of the receptor population. The extent of crosslinking indicated that most of the cell's receptor molecules were organized in higher-order groups. Crosslinking in receptor trimer contact mutants correlated with their signaling behaviors, suggesting that trimers of dimers are both structural and functional precursors of chemoreceptor signaling teams in bacteria.

Bacterial Proteins↗
PubMed1972

Sensitivity of the contact chemoreceptors of the blowfly to vapors.

Contact chemoreceptors on the mouthparts and legs of the blowfly Phormia regina that normally respond to aqueous solutions of sapid substances also respond to compounds in the gaseous state. Effective vapors include organic and inorganic acids and various unrelated nonpolar compounds. In general, the acids stimulate the salt receptor. Some nonpolar compounds stimulate the salt receptor while others inhibit it. Others stimulate the water, sugar, or "fifth" receptor. Differential action cannot be attributed to pH or solubility. Not all compounds that are irritating to mammalian mucous membranes or amphibian skin stimulate the contact chemoreceptors of the fly. Sensitivity to these vapors is a phenomenon analogous to the common chemical sense of vertebrates.

Journal Article↗
PubMed1978

Carotid body chemoreceptor function: hypothesis based on a new circuit model.

Integration of our own morphological observations into recent ultrastructural, biochemical, and neuropharmacological results on the carotid body led to a new hypothesis on chemoreceptor function: (i) Glomus cells with small dense-cored vesicles (type IB cells) that store norepinephrine are chemoreceptors. (ii) Glomus cells with large dense-cored vesicles (type IA), which are postsynaptic to the other glomus cell type and presynaptic to afferent nerve endings, are dopaminergic interneurons that suppress the afferent discharge frequency during normoxia by releasing dopamine. (iii) The hypoxic stimulus causes the chemoreceptive cell to release the stored norepinephrine, which in turn brings about disinhibition of the afferent nerve endings by inhibition of the interneuron. (iv) Afferent nerve endings and interneurons interact through reciprocal synapses that form a short inhibitory feedback loop. We propose that information in the carotid body is processed in a fashion graded rather than digital, providing a fine adjusted cooperation of all elements.

Afferent Pathways↗
PubMed1995

Transmembrane signaling characterized in bacterial chemoreceptors by using sulfhydryl cross-linking in vivo.

Transmembrane signaling by bacterial chemoreceptors is thought to involve conformational changes within a stable homodimer. We investigated the functional consequences of constraining movement between pairs of helices in the four-helix structure of the transmembrane domain of chemoreceptor Trg. Using a family of cysteine-containing receptors, we identified oxidation treatments for intact cells that catalyzed essentially complete sulfhydryl cross-linking at selected positions and yet left flagellar and sensory functions largely unperturbed. Constraining movement by cross-links between subunits had little effect on tactic response, but constraining movement between transmembrane segments of the monomer drastically reduced function. We deduce that transmembrane signaling requires substantial movement between transmembrane helices of a monomer but not between interacting helices across the interface between subunits.

Bacterial Proteins↗
PubMed1997

Uncoupling of ligand-binding affinity of the bacterial serine chemoreceptor from methylation- and temperature-modulated signaling states.

The Escherichia coli chemoreceptor Tsr mediates tactic responses to serine, repellents, and changes in temperature. We have previously shown that the serine-sensing ability of Tsr-T156C, which has a unique cysteine in place of threonine at residue 156, is specifically inactivated by thiol-modifying reagents and that L-serine protects the receptor from modification. In this study, we demonstrated the correlation between protective effects of various attractants and their potencies to elicit attractant responses. This indirect binding assay was used to monitor the affinity of the receptor for L-serine under various conditions. It has been demonstrated by in vitro assays that the ligand-binding affinities of Tsr and the related chemoreceptor Tar are unaffected by changes in the methylation state of the receptor. Using the serine protection assay, we re-examined this issue both in vitro and in vivo. The methylation levels of Tsr-T156C did not affect its ligand-binding affinity. We also showed both in vitro and in vivo that the ligand-binding affinity was unaffected by temperature. These results suggest that the structure of the periplasmic domain of the receptor is uncoupled from the signaling states of the cytoplasmic domain. This ligand-binding assay system should be applicable to other receptors.

Amides↗
PubMed1989

Carotid chemoreceptor function and structure in the atherosclerotic rabbit: respiratory and cardiovascular responses to hyperoxia, hypoxia and hypercapnia.

We tested the following hypothesis: if carotid body blood flow, and hence the relationship of the frequency of discharge in chemoreceptor afferent fibres to arterial PO2, were affected by atherosclerotic change, then a modification of the control of the respiratory and cardiovascular systems might result. Carotid body reflexes were therefore studied in conscious atherosclerotic rabbits and a control group of normal animals breathing 100% O2, three hypoxic gas mixtures to which was added sufficient CO2 to maintain the arterial PCO2 constant, and 2% and 4% CO2 in 21% O2 and N2. When breathing room air, the atherosclerotic rabbits breathed at a higher respiratory frequency and lower tidal volume than the normal animals, although there was no difference in the respiratory minute volume. The respiratory and cardiovascular responses to hyperoxia, isocapnic hypoxia and hypercapnia were essentially the same in both groups of animals. Serial sections of the carotid bodies showed pathological changes including interstitial fibrosis in the caudal part with interstitial haemorrhages. The proximal part of the ascending pharyngeal artery, the vessel supplying the organ, and its origin from the external carotid, and the arterioles in the caudal part of the carotid body were nearly always occluded to a varying extent by atheromatous plaques. The capillaries appeared normal under light microscopy. The rostral-caudal lengths of the carotid bodies were similar in the two groups. We conclude that the peripheral arterial chemoreceptor responses in atherosclerotic rabbits are relatively normal even though the arteries to, and arterioles within, the carotid body are partly occluded.

Animals↗
PubMed2002

Unusual cytochrome a592 with low PO2 affinity correlates as putative oxygen sensor with rat carotid body chemoreceptor discharge.

Light-absorption spectra and afferent chemoreceptor discharge were simultaneously recorded on superfused rat carotid bodies (CBs) under the influence of cytochrome a3-CuB ligands (O2, CN-, CO) in order to identify the primary mitochondrial cytochrome c oxidase (CCO) oxygen sensor. Spectra could be described on the basis of weighted light-absorption spectra of cytochrome b558 of the NAD(P)H oxidase and mitochondrial cytochromes b and c, CCO, cytochrome a3, and an unusual cytochrome a peaking at 592 nm. Discharge signals were deconvoluted into phasic and tonic activity for comparing different CB responses. The spectral weight of cytochrome a592 decreased significantly starting at high PO2 (100 mm Hg) and low sodium cyanide (CN-, 10 mM) accompanied by increasing phasic peak discharge. Combined CO-hypoxia or CO-CN- application inhibited photolysis of CO-stimulated chemoreceptor discharge, revealing photometrically cytochrome a592 as central in oxygen sensing. Control spectra in tissue from sympathetic and nodose ganglia did not show any cytochrome a592 contribution. According to these results, cytochrome a592 is assumed as a unique component of CB CCO, revealing in contrast to other cytochromes an apparent low PO2 and high CN- affinity, probably due to a shortcut of electron flow within CCO between CuA and cytochrome a3-CuB.

Animals↗
PubMed1997

Effects of halothane on the phrenic nerve responses to carbon dioxide mediated by carotid body chemoreceptors in vagotomized dogs.

BACKGROUND: Previous studies in dogs showed that the phrenic nerve response to an acute hypoxic stimulus was dose dependently depressed by 0.5-2.0 minimum alveolar concentration (MAC) of halothane but not abolished. Because a carbon dioxide stimulus is transduced by a different mechanism in the carotid body chemoreceptors (CBCRs) than is a hypoxic stimulus, inhalational anesthetics may preferentially depress one of these transduction processes, the central neuronal processing, or both, of the integrated responses to these two types of inputs. METHODS: Carotid body chemoreceptor stimulation was produced by short (1-1.5 s), bilateral, 100% carbon dioxide in saline infusions into the carotid arteries during neural inspiration in unpremedicated, halothane-anesthetized, paralyzed, vagotomized dogs during constant mechanical ventilation. The phrenic neurogram quantified the neural inspiratory response. Four protocols were performed in the study: (1) the dose-dependent effects of halothane anesthesia (0.5-2.0 MAC) during hyperoxic hypercapnia on phrenic nerve activity, (2) the effects of three background levels of the partial pressure of carbon dioxide (PaCO2) on the magnitude of the carbon dioxide infusion responses at 1 MAC halothane, (3) the effects of anesthetic type on the magnitude of the carbon dioxide infusion response, and (4) the effects of CBCR denervation. RESULTS: Peak phrenic nerve activity (PPA) increased significantly during the carbon dioxide-stimulated phrenic burst in protocols 1-3; after denervation there was no response (protocol 4). Halothane produced a dose-dependent reduction in the PPA of control and carbon dioxide infusion-stimulated phrenic bursts and in the net carbon dioxide response. The net PPA responses for the different PaCO2 background levels were not different but were somewhat larger for sodium thiopental anesthesia than for 1.0 MAC halothane. CONCLUSIONS: The phrenic nerve response to an acute, severe carbon dioxide stimulus was dose dependently depressed by surgical doses of halothane. The observed responses to carbon dioxide infusion were mediated by the CBCRs because they were eliminated by CBCR denervation. These results suggest that the CBCR transduction and central transmission of the carbon dioxide signal in terms of inspiratory excitatory drive are not abolished at surgical levels of halothane anesthesia.

Anesthetics, Inhalation↗
PubMed1985

Respiratory and cardiovascular responses to hyperoxia, hypoxia and hypercapnia in the renal hypertensive rabbit: role of carotid body chemoreceptors.

We tested the hypothesis that in renal hypertension the increased peripheral vascular resistance of neurogenic origin might be due to a reflex through resetting of the carotid body chemoreceptors. The reflex respiratory and cardiovascular functions of the carotid bodies were studied in a one-kidney wrapped hypertension model in conscious rabbits, and compared with a control group of animals, by breathing 100% oxygen, three hypoxic gas mixtures to which were added sufficient CO2 to maintain the PaCO2 constant, and 2 and 4% CO2 in 21% O2 and N2. In the control state (breathing room air) the renal hypertensive animals had a slightly higher respiratory minute volume, a higher level of arterial blood pressure and increased calculated systemic vascular resistance, compared with the normal group, but there was no difference in cardiac output. Hyperoxia had no consistent effect on respiration, heart rate or arterial blood pressure. Increasing degrees of isocapnic hypoxia caused the same degree of hyperventilation and bradycardia in both groups of animals. The arterial blood pressure did not change in either group but there was a transient increase in systemic vascular resistance in the renal hypertensives breathing 9 and 7.5% O2. The respiratory responses to 2 and 4% CO2 were similar in the two groups of animals. In the renal hypertensive animals, serial sections of the carotid bodies showed pathological changes, including subendothelial proliferation in vessels supplying the carotid bodies with narrowing of their lumens, fragmentation of the elastic laminae of the media, hypertrophy of the smooth muscle and extensive fibrosis with occasional haemorrhages. The capillaries, however, were normal. The rostral-caudal lengths of the carotid bodies were similar in the two groups. In view of our findings we conclude that the relatively normal carotid chemoreceptor responses in renal hypertensive rabbits may, in part at least, be the result of the carotid body blood flow through the partially occluded vessels being maintained at near normal levels by the elevated blood pressure.

Animals↗
PubMed2004

Accessibility of introduced cysteines in chemoreceptor transmembrane helices reveals boundaries interior to bracketing charged residues.

Two hydrophobic sequences, 24 and 30 residues long, identify the membrane-spanning segments of chemoreceptor Trg from Escherichia coli. As in other related chemoreceptors, these helical sequences are longer than the minimum necessary for an alpha-helix to span the hydrocarbon region of a biological membrane. Thus, the specific positioning of the segments relative to the hydrophobic part of the membrane cannot be deduced from sequence alone. With the aim of defining the positioning for Trg experimentally, we determined accessibility of a hydrophilic sulfhydryl reagent to cysteines introduced at each position within and immediately outside the two hydrophobic sequences. For both sequences, there was a specific region of uniformly low accessibility, bracketed by regions of substantial accessibility. The two low-accessibility regions were each 19 residues long and were in register in the three-dimensional organization of the transmembrane domain deduced from independent data. None of the four hydrophobic-hydrophilic boundaries for these two membrane-embedded sequences occurred at a charged residue. Instead, they were displaced one to seven residues internal to the charged side chains bracketing the extended hydrophobic sequences. Many hydrophobic sequences, known or predicted to be membrane-spanning, are longer than the minimum necessary helical length, but precise membrane boundaries are known for very few. The cysteine-accessibility approach provides an experimental strategy for determining those boundaries that could be widely applicable.

Amino Acid Sequence↗