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PubMed2006

Adaptational modification and ligand occupancy have opposite effects on positioning of the transmembrane signalling helix of a chemoreceptor.

Sensory systems adapt to persistent stimulation. In the transmembrane receptors of bacterial chemotaxis, adaptation is mediated by methylation at specific glutamyl residues in the cytoplasmic domain. Methylation counteracts effects of ligand binding on functional activities of that domain. Both ligand binding and adaptational modification are thought to act through conformational changes. As characterized for Escherichia coli chemoreceptors, a mechanistically crucial feature of the ligand-induced conformational change is piston sliding towards the cytoplasm of a signalling helix in the periplasmic/transmembrane domain. Adaptational modification could counteract this signalling movement by blocking its influence on the cytoplasmic domain or by reversing it. To investigate, we characterized effects of adaptational modification on the position of the signalling helix in chemoreceptor Trg using rates of disulphide formation between introduced cysteines. We utilized an intact cell procedure in which receptors were in their native, functional state. In vivo rates of disulphide formation between diagnostic cysteine pairs spanning a signalling helix interface changed as a function of adaptational modification. Strikingly, those changes were opposite those caused by ligand occupancy for each diagnostic pair tested. This suggests that adaptational modification resets the receptor complex to its null state by reversal of the conformational change generated by ligand binding.

Cysteine↗
PubMed1981

Effects of beta-endorphin, vasoactive intestinal polypeptide and cholecystokinin octapeptide on cat carotid chemoreceptor activity.

The effects of beta-endorphin, vasoactive intestinal polypeptide (VIP) and cholecystokinin octapeptide (CCK-8) on carotid chemoreceptor activity have been investigated in cats anaesthetized with pentobarbitone. Spontaneous chemoreceptor discharge was decreased by intracarotid injection of beta-endorphin and by low doses of VIP, whereas it was increased by CCK-8 and higher doses of VIP, these effects being relatively long-lasting and often associated with changes in systemic blood pressure. The chemoexcitation evoked by acetylcholine and sodium cyanide was reduced during intracarotid infusion of any of the three peptides studied, and that caused by CO2-saturated Locke solution was reduced by beta-endorphin, largely unaltered by VIP and variably affected by CCK-8. The inhibitory effect of beta-endorphin was greatly reduced by naloxone, implying that it probably involved actions at naloxone-sensitive opiate receptors in the carotid body. Substance P was unable to overcome the chemoinhibitory effect of methionine enkephalin. Possible functions of polypeptides in the carotid body are discussed.

Animals↗
PubMed1966

Comparison of the reflex responses elicited by stimulation of the separately perfused carotid and aortic body chemoreceptors in the dog.

1. In dogs under chloralose and urethane anaesthesia, the carotid and aortic bodies were isolated from the circulation and separately perfused with blood, the composition of which could be controlled at will. The remainder of the systemic circulation was perfused at constant blood flow, thereby enabling the reflex vascular responses to be determined. The systemic venous blood was oxygenated in the isolated perfused lungs of a second dog and the P(O2) and P(CO2) of the systemic arterial blood was maintained constant.2. Using hypoxic hypercapnic blood to stimulate the arterial chemoreceptors, carotid body excitation in spontaneously breathing animals caused an increase in respiratory minute volume approximately seven times larger than that evoked by stimulation of the aortic bodies. Whereas the hyperpnoea of carotid body origin is due to an increase in rate and depth of breathing, that from the aortic bodies is due predominantly to an increase in respiratory frequency.3. Stimulation of the carotid bodies in spontaneously breathing animals caused small variable changes in systemic vascular resistance, whereas stimulation of the aortic bodies invariably increased the vascular resistance.4. When pulmonary ventilation was maintained constant, the vascular response to stimulation of the carotid bodies was considerably modified in that constriction invariably occurred; that from the aortic bodies, however, was little affected. There was now no significant difference in the size of responses from the two groups of chemoreceptors. These constrictor responses represent the primary vascular effects.5. A similar modification of the carotid body vascular response occurred in the spontaneously breathing animal after denervation of the lungs, and is due to abolition of a lung-inflation vasodilator reflex.6. The size of the primary vasoconstrictor responses from the carotid and aortic bodies is reduced by lowering the arterial blood P(CO2).7. The results indicate that there is a fundamental difference in the functions of the carotid and aortic bodies. They exert a quantitatively similar primary control of the ;vasomotor centre' which is in striking contrast to the relatively more powerful influence on respiration by the carotid bodies. In the spontaneously breathing animal, however, the primary vasoconstrictor response from the carotid bodies is offset to a varying degree by the lung-inflation vasodilator reflex initiated by the concomitant hyperpnoea. This is not evident with the aortic bodies because of the relatively weaker respiratory response they evoke.

Animals↗
PubMed1978

Respiratory oscillations in discharge frequency of chemoreceptor afferents in sinus nerve and anaesthetized cats at normal and low arterial oxygen tensions.

1. The discharge of chemoreceptor afferents in preparations of the sinus nerve in spontaneously breathing anaesthetized cats has been subjected to an averaging procedure in records obtained when the animals breathed (a) air and (b) a hypoxic gas mixture. 2. The mean discharge frequency was higher in hypoxia than at normal oxygen tension. 3. Oscillations in chemoreceptor discharge frequency with the same period as respiration were obtained by the averaging procedure both at normal arterial oxygen tensions and in hypoxia, but there was no significant increase in oscillation amplitude with hypoxia. 4. The carotid body response to arterial PCO2 oscillations does not therefore appear to be amplified by hypoxia. This finding is discussed in relation to the reported dependence upon hypoxia of the ventilatory effects of tube breathing in man.

Action Potentials↗
PubMed1994

Inhibition of [3H]catecholamine release and Ca2+ currents by prostaglandin E2 in rabbit carotid body chemoreceptor cells.

Basal release of [3H]catecholamine ([3H]CA) from rabbit carotid bodies (CBs), previously incubated in the presence of [3H]tyrosine, was not significantly modified by prostaglandin E2 (PGE2). On the contrary, PGE2 (3-300 nM) produced a dose-dependent inhibition of the low PO2-evoked release of [3H]CA. The inhibition was greatest (55%) at a low intensity of hypoxic stimulation (incubating solution PO2 approximately 66 mmHg) and decreased with increasing intensities of hypoxia. Chronic denervation of the CB did not modify the response to PGE2. The release of [3H]CA induced by incubating the CBs in a hypercapnic-acidic solution (PCO2 approximately 132 mmHg; pH = 6.60) and by dinitrophenol (100 microM) was not significantly modified by 300 nM PGE2. PGE2 (300 nM) inhibited the release of [3H]CA elicited by incubating the CBs in a high K+ (35 mM)-containing solution. The release response elicited by high K+ (25 mM) was strongly augmented by a dihydropyridine agonist of Ca2+ channels, Bay K 8644, at a concentration of 1 microM. The Bay K 8644 effect was partly inhibited by PGE2 (300 nM). Using whole-cell recordings in freshly dispersed or short-term cultured chemoreceptor cells from adult rabbits it was found that Ca2+ currents (ICa) were reversibly inhibited by bath application of PGE2. A good parallelism exits between the dose-response curves for PGE2 inhibition of ICa in isolated chemoreceptor cells and high extracellular [K+]- or hypoxia-evoked release of [3H]CA from the whole CB.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2006

Cysteine-scanning analysis of the chemoreceptor-coupling domain of the Escherichia coli chemotaxis signaling kinase CheA.

The C-terminal P5 domain of the histidine kinase CheA is essential for coupling CheA autophosphorylation activity to chemoreceptor control through a binding interaction with the CheW protein. To locate P5 determinants critical for CheW binding and chemoreceptor control, we surveyed cysteine replacements at 39 residues predicted to be at or near the P5 surface in Escherichia coli CheA. Two-thirds of the Cys replacement proteins exhibited in vitro defects in CheW binding, either before or after modification with a bulky fluorescein group. The binding-defective sites were widely distributed on the P5 surface and were often interspersed with sites that caused no functional defects, implying that relatively minor structural perturbations, often far from the actual binding site, can influence its conformation or accessibility. The most likely CheW docking area included loop 2 in P5 folding subdomain 1. All but four of the binding-defective P5-Cys proteins were defective in receptor-mediated activation, suggesting that CheW binding, as measured in vitro, is necessary for assembly of ternary signaling complexes and/or subsequent CheA activation. Other Cys sites specifically affected receptor-mediated activation or deactivation of CheA, demonstrating that CheW binding is not sufficient for assembly and/or operation of receptor signaling complexes. Because P5 is quite similar to CheW, whose structure is known to be dynamic, we suggest that conformational flexibility and dynamic motions govern the signaling activities of the P5 domain. In addition, relative movements of the CheA domains may be involved in CheW binding, in ternary complex assembly, and in subsequent stimulus-induced conformational changes in receptor signaling complexes.

Bacterial Proteins↗
PubMed1990

Repellent response functions of the Trg and Tap chemoreceptors of Escherichia coli.

The chemoreceptors responsible for the repellent response of Escherichia coli to phenol were investigated. In the absence of all four known methyl-accepting chemoreceptors (Tar, Tsr, Trg, and Tap), cells showed no response to phenol. However, when Trg, which mediates the attractant response to ribose and galactose, was introduced via a plasmid, the cells acquired a repellent response to phenol. About 1 mM phenol induced a clear repellent response; this response was suppressed by 1 mM ribose. Thus, Trg mediates the repellent response to phenol. Mutant Trg proteins with altered sensing for ribose and galactose showed a normal response to phenol, indicating that the interaction site for phenol differs from that for the ribose- and galactose-binding proteins. Tap, which mediates the attractant response to dipeptides, mediated a weaker repellent response to phenol. Tsr, which mediates the attractant response to serine, mediated an even weaker response to phenol. Trg and Tap were also found to function as intracellular pH sensors. Upon a pH decrease, Trg mediated an attractant response, whereas Tap mediated a repellent response. These results indicate that all the receptors in E. coli have dual functions, mediating both attractant and repellent responses.

Bacterial Proteins↗
PubMed1994

Role of a small cytoplasmic domain in the establishment of serine chemoreceptor membrane topology.

The Escherichia coli serine chemoreceptor takes on a simple membrane topology with two transmembrane segments separating cytoplasmically disposed N and C termini from a central periplasmic domain. We investigated the role of the small N-terminal cytoplasmic domain in membrane insertion using alkaline phosphatase gene fusions. Mutations eliminating the positive charge of the domain altered insertion dramatically, with reciprocal effects on hybrids with periplasmic and C-terminal cytoplasmic fusion junctions. Efficient export of the normally cytoplasmic C-terminal domain required that, in addition to the N-terminal changes, a short amphiphatic sequence at the beginning of the C-terminal domain be also absent. These findings document the importance of the positive character of the N-terminal domain in chemoreceptor membrane insertion and imply that partially redundant sequence information controls the orientation of the second transmembrane segment.

Amino Acid Sequence↗
PubMed1995

In vivo sulfhydryl modification of the ligand-binding site of Tsr, the Escherichia coli serine chemoreceptor.

The Escherichia coli chemoreceptor Tsr mediates an attractant response to serine. We substituted Cys for Thr-156, one of the residues involved in serine sensing. The mutant receptor Tsr-T156C retained serine- and repellent-sensing abilities. However, it lost serine-sensing ability when it was treated in vivo with sulfhydryl-modifying reagents such as N-ethylmaleimide (NEM). Serine protected Tsr-T156C from these reagents. We showed that [3H]NEM bound to Tsr-T156C and that binding decreased in the presence of serine. By pretreating cells with serine and cold NEM, Tsr-T156C was selectively labeled with radioactive NEM. These results are consistent with the location of Thr-156 in the serine-binding site. Chemical modification of the Tsr ligand-binding site provides a basis for simple purification and should assist further in vivo and in vitro investigations of this chemoreceptor protein.

Bacterial Proteins↗
PubMed1995

Sequences determining the cytoplasmic localization of a chemoreceptor domain.

The Escherichia coli serine chemoreceptor (Tsr) is a protein with a simple topology consisting of two membrane-spanning sequences (TM1 and TM2) separating a large periplasmic domain from N-terminal and C-terminal cytoplasmic regions. We analyzed the contributions of several sequence elements to the cytoplasmic localization of the C-terminal domain by using chemoreceptor-alkaline phosphatase gene fusions. The principal findings were as follows. (i) The cytoplasmic localization of the C-terminal domain depended on TM2 but was quite tolerant of mutations partially deleting or introducing charged residues into the sequence. (ii) The basal level of C-terminal domain export was significantly higher in proteins with the wild-type periplasmic domain than in derivatives with a shortened periplasmic domain, suggesting that the large size of the wild-type domain promotes partial membrane misinsertion. (iii) The membrane insertion of deletion derivatives with a single spanning segment (TM1 or TM2) could be controlled by either an adjacent positively charged sequence or an adjacent amphipathic sequence. The results provide evidence that the generation of the Tsr membrane topology is an overdetermined process directed by an interplay of sequences promoting and opposing establishment of the normal structure.

Alkaline Phosphatase↗
PubMed1997

A fragment liberated from the Escherichia coli CheA kinase that blocks stimulatory, but not inhibitory, chemoreceptor signaling.

CheA, a cytoplasmic histidine autokinase, in conjunction with the CheW coupling protein, forms stable ternary complexes with the cytoplasmic signaling domains of transmembrane chemoreceptors. These signaling complexes induce chemotactic movements by stimulating or inhibiting CheA autophosphorylation activity in response to chemoeffector stimuli. To explore the mechanisms of CheA control by chemoreceptor signaling complexes, we examined the ability of various CheA fragments to interfere with receptor coupling control of CheA. CheA[250-654], a fragment carrying the catalytic domain and an adjacent C-terminal segment previously implicated in stimulatory control of CheA activity, interfered with the production of clockwise flagellar rotation and with chemotactic ability in wild-type cells. Epistasis tests indicated that CheA[250-654] blocked clockwise rotation by disrupting stimulatory coupling of CheA to receptors. In vitro coupling assays confirmed that a stoichiometric excess of CheA[250-654] fragments could exclude CheA from stimulatory receptor complexes, most likely by competing for CheW binding. However, CheA[250-654] fragments, even in vast excess, did not block receptor-mediated inhibition of CheA, suggesting that CheA[250-654] lacks an inhibitory contact site present in native CheA. This inhibitory target is most likely in the N-terminal P1 domain, which contains His-48, the site of autophosphorylation. These findings suggest a simple allosteric model of CheA control by ternary signaling complexes in which the receptor signaling domain conformationally regulates the interaction between the substrate and catalytic domains of CheA.

Bacterial Proteins↗
PubMed1999

Enhanced function conferred on low-abundance chemoreceptor Trg by a methyltransferase-docking site.

In Escherichia coli, high-abundance chemoreceptors are present in cellular amounts approximately 10-fold higher than those of low-abundance receptors. These two classes exhibit inherent differences in functional activity. As sole cellular chemoreceptors, high-abundance receptors are effective in methyl-accepting activity, in establishing a functional balance between the two directions of flagellar rotation, in timely adaptation, and in mediating efficient chemotaxis. Low-abundance receptors are not, even when their cellular content is increased. We found that the low-abundance receptor Trg acquired essential functional features of a high-abundance receptor by the addition of the final 19 residues of the high-abundance receptor Tsr. The carboxy terminus of this addition carried a methyltransferase-binding pentapeptide, NWETF, present in high-abundance receptors but absent in the low-abundance class. Provision of this docking site not only enhanced steady-state and adaptational methylation but also shifted the abnormal, counterclockwise bias of flagellar rotation toward a more normal rotational balance and vastly improved chemotaxis in spatial gradients. These improvements can be understood as the result of both enhanced kinase activation by the more methylated receptor and timely adaptation by more efficient methyl-accepting activity. We conclude that the crucial functional difference between the low-abundance receptor Trg and its high-abundance counterparts is the level of methyl-accepting activity conferred by the methyltransferase-docking site.

Amino Acid Sequence↗
PubMed2000

Proteolysis of the McpA chemoreceptor does not require the Caulobacter major chemotaxis operon.

The degradation of the McpA chemoreceptor in Caulobacter crescentus accompanies the swarmer cell to the stalked-cell differentiation event. To further analyze the requirements for its degradation, we have constructed a series of strains that have deletions in the mcpA gene and in the mcpA chemotaxis operon. Internal deletions of the mcpA gene demonstrate that the highly conserved domain (signalling unit) and the methylation domains are not required for cell cycle-regulated proteolysis. The deletion of the chemotaxis operon, which is absolutely required for chemotaxis and McpA chemoreceptor methylation, has no effect on McpA proteolysis.

Bacterial Proteins↗
PubMed2000

Mutational analysis of ligand recognition by tcp, the citrate chemoreceptor of Salmonella enterica serovar typhimurium.

The chemoreceptor Tcp mediates taxis to citrate. To identify citrate-binding residues, we substituted cysteine for seven basic or polar residues that are chosen based on the comparison of Tcp with the well-characterized chemoreceptors. The results suggest that Arg-63, Arg-68, Arg-72, Lys-75, and Tyr-150 (and probably other unidentified residues) are involved in the recognition of citrate.

Amino Acid Sequence↗
PubMed1987

Cardiovascular and respiratory effects of adenosine in conscious man. Evidence for chemoreceptor activation.

The cardiovascular and respiratory effects of intravenous adenosine were studied in conscious normal volunteers. Bolus injections of adenosine increased systolic and diastolic pressures initially (+15 and +13 mm Hg after 100 micrograms/kg) followed by a subsequent reduction in systolic and diastolic pressures (-12 and -16 mm Hg). Heart rate increased during trough blood pressure (R-R interval shortening of 298 msec after 100 micrograms/kg). Adenosine steady-state infusions increased heart rate (+30 beats/min during 140 micrograms/kg/min), systolic pressure (+16 mm Hg), and pulse pressure (+21 mm Hg) but decreased diastolic pressure slightly (-5 mm Hg), resulting in no significant change in mean arterial pressure. Adenosine stimulated respiration, resulting in decreased PaCO2 (41 to 31 mm Hg), increased PaCO2 (101 to 113 mm Hg), and increased pH (7.42 to 7.50). The increased ventilation was not explained by bronchoconstriction, hypotension, or hypoxia. The observed pressor and tachycardic effects are mediated through reflex autonomic mechanisms since they are completely abolished in patients with severe autonomic failure. These autonomic mechanisms probably involve chemoreceptor activation since adenosine is pressor when infused in the aortic arch proximal to the origin of the carotid arteries but depressor when infused in the descending aorta. It is concluded that the hemodynamic and respiratory effects of adenosine observed in normal volunteers are in part due to chemoreceptor stimulation. These findings raise the possibility that adenosine is an endogenous modulator of respiration in man.

Adenosine↗
PubMed1976

Role of the chemoreceptor in diving bradycardia in rat.

Responses in heart rate and blood pressure to the dive in unanesthetized rats were studied by submersion of the head in water for 30 sec. During the dive, remarkable bradycardia developed and blood pressure was slightly elevated. Bilateral section of the carotid sinus nerves or selective destruction of the carotid body chemoreceptor by intrasinusal injection of acetic acid attenuated the bradycardic response to the dive, while section of the recurrent nerves or section of the sympathetic trunks at the cervical level together with the superior laryngeal nerves had no effect. These data indicate that the chemoreceptor plays an important role in diving bradycardia in rats.

Animals↗
PubMed1980

Chemoreceptor tumors diagnosed at the Western College of Veterinary Medicine 1967-1979.

Twenty-nine chemoreceptor tumors submitted to the Western College of Veterinary Medicine, Saskatoon, Saskatchewan between 1967 and 1979 were compared with those previously reported. The prevalence was low, with 28 cases occurring in dogs while only one was diagnosed in a cat. Old male dogs and the Boxer, Boston bull terrier and Collie breeds were affected most commonly. The prevalence in Collies (five of 28 dogs) was unexpected but may have been coincidental in this size of sample. The chemoreceptor tumor was often of clinical significance because in two-thirds of the cases it was either the presenting complaint or considered at necropsy to have caused illness or death.

Age Factors↗
PubMed1995

Distribution of epithelioid cells in the wall of the chicken aorta and their functional role as chemoreceptors.

BACKGROUND: The ultrastructural characteristics of epithelioid cells in the wall of the chicken aorta have been studied by several investigators. Their characteristics were homologous to those of carotid body type I cells and are considered to be one of the peripheral chemoreceptors. However, there are few descriptions about their location, distribution, and how they react to chemical signals, nor have there been many reports about the localization of bioactive substances in the epithelioid cells. Therefore we designed this investigation to address these problems. METHODS: Wholemount immunohistochemistry using antiserotonin antiserum, scanning (SEM), and transmission (TEM) electron microscopy were used to observe the epithelioid cells and the lumen of the chicken aorta. The localizations of bioactive substances in the epithelioid cells were immunohistochemically investigated using 11 antisera. RESULTS: Epithelioid cells were dispersed in the wall of the aorta, forming a band approximately 1 mm in width, located 10 mm proximal to the confluence of the right and left ligamenta arteriosa. Serotonin, chromogranin, and neuron specific enolase immunoreactivities were detected in the epithelioid cells. SEM observations clearly demonstrated intraendothelial fenestrations, 1-3 microns in diameter, on the endothelial surface of the region of the band of epithelioid cells. TEM observations revealed that these fenestrations corresponded to endothelial gaps, directly beneath which epithelioid cells were sometimes located. CONCLUSIONS: The epithelioid cells are in direct access to the aortic lumen through endothelial fenestrations. Thus they may be able to perceive chemical signals from arterial blood directly.

Animals↗