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PubMed2002

CheA kinase and chemoreceptor interaction surfaces on CheW.

Chemotactic responses of Escherichia coli to aspartic acid are initiated by a ternary protein complex composed of Tar (chemoreceptor), CheA (kinase), and CheW (a coupling protein that binds to both Tar and CheA and links their activities). We used a genetic selection based on the yeast two-hybrid assay to identify nine cheW point mutations that specifically disrupted CheW interaction with CheA but not with Tar. We sequenced these single point mutants and purified four of the mutant CheW proteins for detailed biochemical characterizations that demonstrated the weakened affinity of the mutant CheW proteins for CheA, but not for Tar. In the three-dimensional structure of CheW, the positions affected by these mutations cluster on one face of the protein, defining a potential binding interface for interaction of CheW with CheA. We used a similar two-hybrid approach to identify four mutation sites that disrupted CheW binding to Tar. Mapping of these "Tar-sensitive" mutation sites and those from previous suppressor analysis onto the structure of CheW defined an extended surface on a face of the protein that is adjacent to the CheA-binding surface and that may serve as an interface for CheW binding to Tar.

Bacterial Proteins↗
PubMed1989

Ionic currents in dispersed chemoreceptor cells of the mammalian carotid body.

Ionic currents of enzymatically dispersed type I and type II cells of the carotid body have been studied using the whole cell variant of the patch-clamp technique. Type II cells only have a tiny, slowly activating outward potassium current. By contrast, in every type I chemoreceptor cell studied we found (a) sodium, (b) calcium, and (c) potassium currents. (a) The sodium current has a fast activation time course and an activation threshold at approximately -40 mV. At all voltages inactivation follows a single exponential time course. The time constant of inactivation is 0.67 ms at 0 mV. Half steady state inactivation occurs at a membrane potential of approximately -50 mV. (b) The calcium current is almost totally abolished when most of the external calcium is replaced by magnesium. The activation threshold of this current is at approximately -40 mV and at 0 mV it reaches a peak amplitude in 6-8 ms. The calcium current inactivates very slowly and only decreases to 27% of the maximal value at the end of 300-ms pulses to 40 mV. The calcium current was about two times larger when barium ions were used as charge carriers instead of calcium ions. Barium ions also shifted 15-20 mV toward negative voltages the conductance vs. voltage curve. Deactivation kinetics of the calcium current follows a biphasic time course well fitted by the sum of two exponentials. At -80 mV the slow component has a time constant of 1.3 +/- 0.4 ms whereas the fast component, with an amplitude about 20 times larger than the slow component, has a time constant of 0.16 +/- 0.03 ms. These results suggest that type I cells have predominantly fast deactivating calcium channels. The slow component of the tails may represent the activity of a small population of slowly deactivating calcium channels, although other possibilities are considered. (c) Potassium current seems to be mainly due to the activity of voltage-dependent potassium channels, but a small percentage of calcium-activated channels may also exist. This current activates slowly, reaches a peak amplitude in 5-10 ms, and thereafter slowly inactivates. Inactivation is almost complete in 250-300 ms. The potassium current is reversibly blocked by tetraethylammonium. Under current-clamp conditions type I cells can spontaneously fire large action potentials. These results indicate that type I cells are excitable and have a variety of ionic conductances. We suggest a possible participation of these conductances in chemoreception.

Animals↗
PubMed1976

The effect of halothane and thiopentone on ventilatory responses mediated bythe peripheral chemoreceptors in man.

The activity and responsiveness of the peripheral ventilatory chemoreflex were assessed by the transient depression of ventilation following two breaths of oxygen in air-breathing subjects, and the differing times of onset of the ventilatory response to i.v. sodium bicarbonate in subjects breathing either air or oxygen. In patients premedicated with pethidine, in whom anaesthesia was induced with thiopentone, it was found that halothane, in an inspired concentration of 0.7-0.8%, reduced the activity and responsiveness of the peripheral ventilatory chemoreflex markedly. When halothane was discontinued and anaesthesia was maintained wtih intermittent injections of thiopentone (0.2 mg/kg/min) evidence of peripheral chemoreceptor activity and responsiveness returned.

Adult↗
PubMed1976

Stimulation of the peripheral chemoreceptors with sodium bicarbonate.

The i.v. administration of sodium bicarbonate was found to cause an increase in arterial pH, followed by an increase in PaCO2. This caused a large increase in lung ventilation in in PaO2. Oxygen administration in human subjects, and anatomical denervation of the chemoreceptors in dogs, caused a substantial delay in the ventilatory responses to sodium bicarbonate. It was concluded that the i.v. administration of sodium bicarbonate provides a method of testing the presence of peripheral chemoreflexes which has the advantage of being independent of alveolar ventilation.

Adult↗
PubMed1977

Evidence of a role for the peripheral chemoreceptors in the ventilatory response to doxapram in man.

In seven normal subjects premedicated with atropine and pethidine and lightly anesthetized with thiopentone, the ventilatory response evoked by doxapram 20 mg i.v. was delayed on average from 15.7 s to 23.0 s when changing from air to oxygen breathing. Mean VE, immediately after the administration of doxapram was increased by 3.3 litre and 1.9 litre when breathing air and oxygen respectively. These findings indicate that doxapram has an effect on the peripheral chemoreceptors and are consistent with drug activity on both peripheral and central respiratory control mechanisms.

Adult↗
PubMed1989

Effect of thiopentone, etomidate and propofol on carotid body chemoreceptor activity in the rabbit and the cat.

The response of the carotid body chemoreceptors to intracarotid administration of thiopentone, etomidate and propofol was tested in the rabbit and cat. Thiopentone 3-6 mg min-1 and etomidate 300-600 micrograms min-1 were mildly excitatory, shifting the oxygen and carbon dioxide response curves upwards. Propofol 1.5-3.0 mg min-1 was a potent chemodepressant and abolished discharge at PaO2 values greater than 8 kPa. Prolonged infusion of propofol at higher rates (6 mg min-1) abolished the response to hypoxia completely. The significance of these results is discussed in relation to the known ventilatory effects of the three anaesthetics.

Action Potentials↗
PubMed1993

Chronic hypoxia in vitro increases volume of dissociated carotid body chemoreceptors.

Exposure of humans or animals to chronic hypoxia results in enlargement of the carotid body, a respiratory organ that controls ventilation. The underlying mechanisms are unclear but involve hypertrophy of the chemoreceptor glomus cells. To test whether the latter response can occur independent of the circulation or neural inputs, we exposed cultures of dissociated rat carotid body to chronic hypoxia (2-3 weeks in 6% O2), and compared the 3-D cell volume of immunofluorescent, tyrosine hydroxylase positive (TH+) glomus cells, from data sets obtained by serial confocal microscopy. We found a dramatic increase in volume (3-4 x control) of hypoxia-treated TH + cells, suggesting that glomus cell hypertrophy during chronic hypoxia in vivo is likely due to a local effect of low PO2, rather than the production of ectopic growth factors.

Animals↗
PubMed1999

Role of ET-1 in hypoxia-induced mitosis of cultured rat carotid body chemoreceptors.

The mammalian carotid body (CB) contains O2-chemoreceptors, i.e. glomus cells, which display increased mitoses and endothelin-1 (ET-1) expression during chronic hypoxia. To investigate whether endogenous ET-1 might mediate these mitogenic effects, we quantified bromodeoxyuridine (BrdU) uptake by tyrosine hydroxylase (TH)-positive glomus cells in rat CB cultures using double-label immunofluorescence. In normoxia (20% O2), 2-day exposure to ET-1 (10-1000 nM) caused a dose-dependent increase in BrdU uptake which peaked (approximately 55% of TH+ cells) at around 500 nM ET-1. In chronic hypoxia (5% O2) alone, BrdU uptake was stimulated (approximately 46% of TH+ cells) relative to normoxia (approximately 30%), but the effect was abolished in the presence of specific (BQ 123) or non-specific (PD 142893) ETA receptor antagonists (10(-5) M). Thus paracrine/autocrine release of ET-1 in the hypoxic carotid body may promote glomus cell mitosis via ET(A) receptors.

Animals↗
PubMed2000

The large srh family of chemoreceptor genes in Caenorhabditis nematodes reveals processes of genome evolution involving large duplications and deletions and intron gains and losses.

The srh family of chemoreceptors in the nematode Caenorhabditis elegans is very large, containing 214 genes and 90 pseudogenes. It is related to the str, stl, and srd families of seven-transmembrane or serpentine receptors. Like these three families, most srh genes are concentrated on chromosome V, and mapping of their chromosomal locations on a phylogenetic tree reveals 27 different movements of genes to other chromosomes. Mapping of intron gains and losses onto the phylogenetic tree reveals that the last common ancestral gene of the family had five introns, which are inferred to have been lost 70 times independently during evolution of the family. In addition, seven intron gains are revealed, three of which are fairly recent. Comparisons with 20 family members in the C. briggsae genome confirms these patterns, including two intron losses in C. briggsae since the species split. There are 14 clear C. elegans orthologs for these 20 genes, whose average amino acid divergence of 68% allows estimation of 85 gene duplications in the C. elegans lineage since the species split. The absence of six orthologs in C. elegans also indicates that gene loss occurs; consideration of all deletions and terminal truncations of srh pseudogenes reveals that large deletions are common. Together these observations provide insight into the evolutionary dynamics of this compact animal genome.

Amino Acid Sequence↗
PubMed2006

Midazolam depresses carotid body chemoreceptor activity.

BACKGROUND: Although the contribution of the gamma-aminobutyric acid (GABA) receptor system in peripheral chemosensation is unclear, immunohistochemistry has demonstrated the presence of GABA-ergic receptors in mammalian carotid bodies. We hypothesized that an activation of the carotid body GABA receptors would counteract the depolarizing effect of hypoxia. METHODS: The carotid body with arterial supply and the carotid sinus nerve was removed en bloc from New Zealand White rabbits and placed in a perfusion chamber. The carotid body preparation was perfused via the cut common carotid artery with a modified Tyrode's solution at a rate of 3.5-4.5 ml/min with a constant pressure of 45 cmH2O. The carotid sinus nerve firing frequency (Hz) was recorded at two different oxygen tension levels during perfusion with midazolam of 1, 10 and 100 microg/l. RESULTS: The frequency was decreased by midazolam in a dose-dependent manner (n = 8). Firing frequencies (mean +/- SEM) at the low oxygen tension level decreased from 643.13 +/- 67.2 Hz in the control to 554.5 +/- 67.7 Hz (P = 0.054 vs. control), 509.01 +/- 100.5 Hz (P < 0.012 vs. control) and 422.6 +/- 77.3 Hz (P < 0.001 vs. control) during perfusion with midazolam of 1, 10 and 100 microg/l, respectively. CONCLUSION: Midazolam depresses carotid body chemoreceptor activity in a dose-dependent manner.

Action Potentials↗
PubMed1995

Alteration of baroreceptor and chemoreceptor reflexes in spontaneously hypertensive rats.

1. Electrical stimulation of the aortic depressor nerve elicited depressor and bradycardiac responses in both spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats, but in spontaneously breathing animals responses were weaker in SHR than in WKY. 2. Responses did not significantly differ in artificially ventilated animals except that high stimulation intensity elicited significantly greater bradycardiac responses in WKY. A decrease in ventilatory rate occurred in both strains. 3. Electrical stimulation of the carotid sinus nerve (CSN) elicited an initial pressor response followed by a depressor response with a minimal change in heart rate in either strain. The pressor response in SHR was greater than in WKY. Depressor responses in SHR were weaker than those in WKY with or without artificial ventilation. CSN stimulation increased ventilatory rate in both strains but the frequency-related responses differed at higher stimulation intensity. 4. These results suggest that there are alterations in the function of central or afferent components of chemoreceptor and baroreceptor reflexes in SHR in addition to previously described structural changes at the level of peripheral sensory receptors.

Animals↗
PubMed1998

Ventral medullary chemoreceptor inputs to neurons within the nucleus ambiguus.

1. The neural mechanisms by which neurons within the nucleus ambiguus respond to chemoreceptor stimuli applied to the ventral medullary surface (VMS) were investigated by determining the effect of low pH on the membrane potential and synaptic activity of these neurons in vitro. 2. Small reductions in pH evoked an indirect membrane depolarization and/or an increase in excitatory synaptic activity in the majority of neurons. A direct membrane hyperpolarization was observed in the remaining neurons. 3. Acetylcholine evoked a direct nicotinic receptor-mediated membrane depolarization in these neurons. In addition, 37% of neurons received muscarinic synaptic input that originated from neurons located near the VMS. 4. Low-pH artificial cerebrospinal fluid (aCSF) potentiated the cholinergic component of the excitatory post-synaptic potential (EPSP) evoked from near the VMS. Both this EPSP and the spontaneous EPSP evoked by low-pH aCSF could be blocked by atropine. 5. It is concluded that at least two different mechanisms exist to transmit chemoreceptive information from the VMS to neurons within the nucleus ambiguus. In the majority of neurons, an indirect excitatory response is observed that is due, in part, to activation of a polysynaptic cholinergic pathway originating near the VMS. In the remaining neurons, low pH evokes a hyperpolarization that is due to a direct action of the dendrites of the neurons themselves that project near to the VMS.

Acetylcholine↗
PubMed1998

Co-activation of tongue protrudor and retractor muscles during chemoreceptor stimulation in the rat.

1. Our primary purpose was to test the hypothesis that the tongue protrudor (genioglossus, GG) and retractor (styloglossus, SG and hyoglossus, HG) muscles are co-activated when respiratory drive increases, and that co-activation will cause retraction of the tongue. This was addressed by performing two series of experiments using a supine, anaesthetized, tracheotomized rat in which tongue muscle force and the neural drive to the protrudor and retractor muscles could be measured during spontaneous breathing. In the first series of experiments, respiratory drive was increased progressively by occluding the tracheal cannula for thirty respiratory cycles; in the second series of experiments, the animals were subjected to hyperoxic hypercapnia and poikilocapnic hypoxia. 2. Airway occlusion for thirty breaths caused progressive, quantitatively similar increases in efferent motor nerve activity to protrudor and retractor tongue muscles. Net tongue muscle force was always consistent with tongue retraction during occlusion, and peak force rose in parallel with the neural activites. When airway occlusion was repeated following section of the lateral XIIth nerve branch (denervation of retractor muscles) the tongue either protruded (15/21 animals; 10 +/- 2 mN at the 30th occluded breath) or retracted weakly (6/21 animals; 6 +/- 2 mN at 30th occluded breath). 3. To ensure that our findings were not the result of damage to the muscle nerves, occlusion experiments were also done in eight animals in which GG EMG activity was recorded instead of nerve activities. Changes in peak integrated GG electryomyogram (EMG) activity and peak retraction force during occlusion were highly correlated (r2 = 0.86, slope = 1.05). 4. In separate experiments in fourteen rats, we found that hyperoxic hypercapnia and poikilocapnic hypoxia also result in parallel increases in the respiratory-related EMG activity of the GG and HG muscles. Also, as in the occlusion experiments, augmentations of protrudor and retractor muscle EMG activities were associated with parallel changes in tongue retraction force. 5. These studies in anaesthetized rats demonstrate that tracheal occlusion and independent stimulation of central or peripheral chemoreceptors results in inspiratory-related co-activation of the protrudor and retractor muscles, and proportional changes in tongue retraction force. These observations also demonstrate that recording GG EMG activity in isolation could lead to erroneous conclusions about respiratory-related movements of the tongue.

Airway Obstruction↗
PubMed1999

Characteristics of 5-HT-containing chemoreceptor cells of the chicken aortic body.

1. Voltage-dependent and oxygen-sensitive currents in 5-HT-containing epithelioid cells isolated from chicken thoracic aorta were examined using the whole-cell patch clamp technique. 5-HT immunoreactive cells were identified with Neutral Red. The release of 5-HT from chicken thoracic aorta in the presence of excess KCl and veratridine was also examined using HPLC. 2. At a holding potential of -70 mV with CsCl pipette solution, depolarizing steps between -30 and +60 mV produced inward currents that were blocked by tetrodotoxin (0.2 microM). In the presence of tetrodotoxin and BaCl2 (5 mM), depolarizing steps evoked slow inward currents that were sensitive to CoCl2 (2 mM). Nifedipine (1 microM) decreased the currents to 79.4 +/- 1.7 %, and omega-conotoxin GVIA (1 microM) to 20.2 +/- 3.8 %. 3. When KCl pipette solution was used, depolarizing potentials positive to -40 mV caused outward currents that were inhibited by tetraethylammonium chloride. The K+ currents evoked by depolarizing steps to +20 mV were reduced to 90.3 +/- 0.8 % by hypoxia in five out of seven cells. Two cells failed to respond to hypoxia. The K+ current response was partly decreased by Neutral Red (20 microM). 4. Excess KCl (60 mM) and veratridine (30 microM) both caused the release of 5-HT from aortic strips. 5-HT outputs induced by both stimuli were partly inhibited by nifedipine (1 microM) and by omega-conotoxin GVIA (1 microM), and were abolished by these drugs in combination and by extracellular Ca2+ removal. 5. These results suggest that epithelioid cells containing 5-HT act as chemoreceptor cells in the chicken aortic body, having voltage-dependent Na+, K+, and L- and N-type Ca2+ channels, and oxygen-sensitive K+ channels.

Animals↗
PubMed1999

Resetting and postnatal maturation of oxygen chemosensitivity in rat carotid chemoreceptor cells.

1. Carotid chemoreceptor sensitivity is minimal immediately after birth and increases with postnatal age. In the present study we have investigated the peri- and postnatal developmental time course of [Ca2+]i responses to hypoxia in clusters of type I cells isolated from near-term fetal rats and rats that were 1, 3, 7, 11, 14 and 21 days old, using the Ca2+-sensitive fluoroprobe fura-2. 2. In type I cells from all age groups a graded increase in [Ca2+]i occurred in response to lowering the PO2 from 150 mmHg to 70, 35, 14, 7, 2 and 0 mmHg. The graded [Ca2+]i response to hypoxia was hyperbolic at all ages. 3. Type I cells from rats near-term fetal to 1 day old exhibited small [Ca2+]i responses, mainly to the most severe levels of hypoxia. After day 1, an increase in the [Ca2+]i responses to submaximal hypoxia stimulation resulted in a rightward shift in the O2 response curve. Using the Delta[Ca2+]i between 35 and 2 mmHg PO2 as an index of O2 sensitivity, type I cell O2 sensitivity increased approximately 4- to 5-fold between near-term fetal to 1 day old and 11 to 14 days of age. 4. Exposure to elevated extracellular potassium (10, 20 and 40 mM K+) caused a dose-dependent [Ca2+]i rise in type I cells from all age groups. There were no age-related changes in [Ca2+]i responses to any level of K+ between near-term fetal and 21 days. 5. We conclude that the maximal type I cell [Ca2+]i response to anoxia, as well as the sensitivity to submaximal hypoxic stimulation, of rats aged from near-term fetal to 21 days depends on the level of postnatal maturity. The lack of an age-related increase in the [Ca2+]i response to elevated K+ during the timeframe of maximal development of O2 sensitivity suggests that resetting involves maturation of O2 sensing, rather than non-specific developmental changes in the [Ca2+]i rise resulting from depolarization.

Aging↗
PubMed2000

Co-release of ATP and ACh mediates hypoxic signalling at rat carotid body chemoreceptors.

Using functional co-cultures of rat carotid body (CB) O2 chemoreceptors and 'juxtaposed' petrosal neurones (JPNs), we tested whether ATP and ACh acted as co-transmitters. Perforated-patch recordings from JPNs often revealed spontaneous and hypoxia-evoked (PO2 approximately 5 mmHg) excitatory postsynaptic responses. The P2X purinoceptor blocker, suramin (50 microM) or a nicotinic ACh receptor (nAChR) blocker (hexamethonium, 100 microM; mecamylamine, 1 microM) only partially inhibited these responses, but together, blocked almost all activity. Under voltage clamp (-60 mV), fast perfusion of 100 microM ATP over hypoxia-responsive JPNs induced suramin-sensitive (IC50 = 73 microM), slowly-desensitizing, inward currents (IATP) with time constant of activation tauon = 30.6 +/- 4. 8 ms (n = 7). IATP reversed at 0.33 +/- 3.7 mV (n = 4), and the dose-response curve was fitted by the Hill equation (EC50 = 2.7 microM; Hill coefficient approximately 0.9). These purinoceptors contained immunoreactive P2X2 subunits, but their activation by alpha,beta-methylene ATP (alpha,beta-meATP; EC50 = 2.1 microM) suggests they are P2X2/P2X3 heteromultimers. Suramin and nAChR blockers inhibited the extracellular chemosensory discharge in the intact rat carotid body-sinus nerve preparation in vitro. Further, P2X2 immunoreactivity was widespread in rat petrosal ganglia in situ, and co-localized in neurones expressing the CB chemo-afferent marker, tyrosine hydroxylase (TH). P2X2 labelling in the CB co-localized with nerve-terminal markers, and was intimately associated with TH-positive type 1 cells. Thus ATP and ACh are co-transmitters during chemotransduction in the rat carotid body.

Acetylcholine↗
PubMed1990

Is central chemoreceptor sensitive to intracellular rather than extracellular pH?

The chemosensitive area on the ventral surface of the brain stem responds to local acidosis by eliciting hyperventilation and to local alkalosis by hypoventilation. The stimulus is conventionally thought to be the hydrogen ion concentration in the area's extracellular fluid. It is pointed out, however, that the elegant studies by Loeschcke & Ahmad have demonstrated that [pH]e and [pH]i are normally tightly and rapidly coupled (Loeschcke & Ahmad, 1980). For this reason, the stimulus might just as well be the intracellular hydrogen ion concentration in the chemoreceptor area. The administration of acetazolamide allows the dissociation of [pH]e from [pH]i. With acetazolamide a sharp acid shift of CSF pH [( pH]c) is measured and in two consonance with this shift a marked increase in CBF is seen. Comparing these two reactions to that obtained with CO2 breathing, it is apparent that 7% CO2 causes about the same decrease in [pH]e and the same increase in CBF. In other words CBF acidosis can quantitatively account for the CBF increase induced by acetazolamide. But CO2 and acetazolamide influence [pH]i quite differently, as CO2 drops [pH]i to almost the same extent as [pH]c, while two recent studies by MR spectroscopy have shown that acetazolamide does not drop [pH]i measurably, if tissue hypercapnia is prevented in artificially ventilated rabbits or by the mild spontaneous hyperventilation caused by acetazolamide in normal man.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetazolamide↗