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PubMed2006

Isolation and characterization of putative O2 chemoreceptor cells from the gills of channel catfish (Ictalurus punctatus).

Little is known about the cells or mechanisms of O2 chemoreception in vertebrates other than mammals. The purpose of this study, therefore, was to identify O2-sensitive chemoreceptors in a fish. Putative O2-sensitive chemoreceptors were dissociated from the gills of channel catfish, Ictalurus punctatus, and cultured. A population of cells was identified with morphology and a histochemical profile similar to mammalian carotid body Type I (glomus) cells and pulmonary neuroepithelial cells. These cells stain with neutral red and appear to be the branchial neuroepithelial cells. Immunocytochemical staining showed that these cells contain neuron-specific enolase (NSE), tyrosine hydroxylase (TH) and 5-hydroxytryptamine (5HT). Patch-clamp experiments showed that these cells have a O2-sensitive, voltage-dependent outward K+ current like mammalian O2 sensors. Two kinds of electrophysiological responses to hypoxia (P(O2) < 10 Torr) were observed. Some cells showed inhibition of outward current in response to hypoxia, whereas other cells showed potentiation. Neurochemical content and electrophysiological responses to hypoxia indicate that these cells are piscine O2-sensitive chemoreceptors.

Animals↗
PubMed1998

Neurons in the posterior insular cortex are responsive to gustatory stimulation of the pharyngolarynx, baroreceptor and chemoreceptor stimulation, and tail pinch in rats.

Extracellular unit responses to gustatory stimulation of the pharyngolaryngeal region, baroreceptor and chemoreceptor stimulation, and tail pinch were recorded from the insular cortex of anesthetized and paralyzed rats. Of the 32 neurons identified, 28 responded to at least one of the nine stimuli used in the present study. Of the 32 neurons, 11 showed an excitatory response to tail pinch, 13 showed an inhibitory response, and the remaining eight had no response. Of the 32 neurons, eight responded to baroreceptor stimulation by an intravenous (i.v.) injection of methoxamine hydrochloride (Mex), four were excitatory and four were inhibitory. Thirteen neurons were excited and six neurons were inhibited by an arterial chemoreceptor stimulation by an i.v. injection of sodium cyanide (NaCN). Twenty-two neurons were responsive to at least one of the gustatory stimuli (deionized water, 1.0 M NaCl, 30 mM HCl, 30 mM quinine HCl, and 1.0 M sucrose); five to 11 excitatory neurons and three to seven inhibitory neurons for each stimulus. A large number of the neurons (25/32) received converging inputs from more than one stimulus among the nine stimuli used in the present study. Most neurons (23/32) received converging inputs from different modalities (gustatory, visceral, and tail pinch). The neurons responded were located in the insular cortex between 2.0 mm anterior and 0.2 mm posterior to the anterior edge of the joining of the anterior commissure (AC); the mean location was 1.2 mm (n=28) anterior to the AC. This indicates that most of the neurons identified in the present study seem to be located in the region posterior to the taste area and anterior to the visceral area in the insular cortex. These results indicate that the insular cortex neurons distributing between the taste area and the visceral area receive convergent inputs from gustatory, baroreceptor, chemoreceptor, and nociceptive organs.

Animals↗
PubMed1996

Role of aortic chemoreceptors in the hypertensive response to cigarette smoke.

To determine the role of aortic chemoreceptors in the rise of systemic blood pressure (BP) seen with smoking cigarettes, their responses to injecting various doses of nicotine (Nic) into the left atrium and to a puff of cigarette smoke were studied in 31 cats. The activity of 71% (n = 36) of the chemoreceptor fibres was stimulated significantly by a puff of cigarette smoke (delivering approximately 10.0 micrograms kg-1 Nic). The mean threshold dose to stimulation by nicotine of these fibres was 8.0 micrograms kg-1. The activity of the remaining 29% (n = 15) was not stimulated; their mean threshold dose to stimulation by Nic was 24 micrograms kg-1. Stimulation of fibres lasted for about 14 +/- 0.2 sec and the rise in BP was seen for 20-60 sec. By using hexamethonium it was established that the stimulation was produced exclusively by Nic contained in cigarette smoke. It was concluded that aortic chemoreceptors must contribute to the reflex rise in BP produced by smoking cigarettes.

Animals↗
PubMed1998

Integration of bronchomotor and ventilatory responses to chemoreceptor stimulation in developing sheep.

We analyzed the changes induced by central chemoreceptor stimulation on the lung resistances and phrenic neurogram of anesthetized newborn (3-6 days, n = 9) and 9 week old lambs (n = 3). Starting from hypocapneic apnea, 5% CO2 inhalation evoked a reversible increase in total lung resistance in both newborn and 9 week old lambs (median = 112%). The resistance increase preceded phrenic breathing and was greater for the peripheral (233%) than for the central airways (57%), independent of age. Increases in lung and airway resistance caused by CO2 were reversed totally by atropine and only partially by apnea-producing doses of fentanyl. Our results demonstrate that parasympathetic outflow to the sheep airways is already driven by central chemoreceptor inputs during the newborn period. Even at this early age, bronchomotor responses to central chemoreceptor stimulation are more prominent in the peripheral than in the central airways and exhibit a lower threshold for activation and less sensitivity to opioid inhibition than phrenic responses.

Airway Resistance↗
PubMed1999

Redox-dependent binding of CO to heme protein controls P(O2)-sensitive chemoreceptor discharge of the rat carotid body.

Simultaneous recordings of chemoreceptor discharge and redox state of cytochromes have been carried out on the rat carotid body in vitro under the influence of carbon monoxide (CO) in order to identify the primary oxygen sensor protein controlling transmitter release and electrical activity. CO excites in a photolabile manner chemoreceptor discharge under normoxic conditions and inhibits under hypoxic conditions probably by binding to heme proteins. We hypothesize that type I cells and adjacent nerve endings of the carotid body tissue have a different apparatus with oxygen sensing heme proteins to cooperate for the generation of peripheral chemoreceptor response. Transmitter release from type I cells might be established in a redox dependent manner whereas membrane potential of nerve endings might be controlled by a heme coupled to ion channels.

Animals↗
PubMed2000

Important role of carotid chemoreceptor afferents in control of breathing of adult and neonatal mammals.

This review provides a summary and prospective on the importance of carotid/peripheral chemoreceptors to the control of breathing during physiologic conditions. For several days after carotid body denervation (CBD), adult mammals hypoventilate (+10 mmHg increase in Pa(CO(2))) at rest and during exercise and CO(2) sensitivity is attenuated by about 60%. In addition, if the rostral ventrolateral medulla is cooled during NREM sleep after CBD, a sustained apnea is observed. Eventually, days or weeks after CBD, a peripheral ventilatory chemoreflex redevelops and there is a normalization of breathing (rest and exercise) and CO(2) sensitivity. The site (s) of the regained chemosensitivity has not been established. This plasticity/redundancy after CBD appears greater in neonates than in adult mammals. These data suggest the carotid and other peripheral chemoreceptors provide an important excitatory input to medullary respiratory neurons that is essential for breathing when wakeful stimuli and central chemoreceptors are absent.

Aging↗
PubMed2000

Peripheral chemoreceptor activation enhances 5-hydroxytryptamine release in the locus coeruleus of conscious rats.

Intravenous bolus injection of KCN (40 microg) elicited brief but pronounced tachypnea, bradycardia and pressor response, and led to a 37% increase in 5-hydroxytryptamine (serotonin) (5-HT) release in the locus coeruleus (LC) of freely moving rats. Slow infusion of KCN (15 microg/min) for 10 min induced only a slight pressor response, but increased the respiration rate (+39 breaths/min), as well as 5-HT release in the LC (+60%) throughout the infusion. In rats with transected chemoreceptor afferents, neither injection or infusion of KCN changed 5-HT release, suggesting that in intact animals, the effect on extracellular 5-HT was due to activation of peripheral chemoreceptors. In summary, we report that peripheral chemoreceptor activation enhances 5-HT release in the LC, indicating that 5-HT might be involved in the modulation of LC activity by ascending chemosensory information.

Animals↗
PubMed1997

Evidence for the involvement of endogenous aspartate in the mediation of carotid chemoreceptor reflexes in the rostral ventrolateral medulla of the rat.

2-Amino-5-phosphonovalerate (AP5; 153 pmol) injected into the rostral ventrolateral medulla (RVLM) inhibited pressor responses induced by carotid chemoreceptor stimulation. AP5 also inhibited pressor responses to aspartate (0.75 nmol) but not to glutamate (0.53 nmol) similarly injected. High K+ (50 mM) released endogenous aspartate and glutamate in a Ca2+-dependent manner from the RVLM. Chemoreceptor stimulation caused a release of aspartate but not of glutamate in the RVLM, and sinus nerve denervation abolished the release of aspartate. Increases in blood pressure induced by intravenous phenylephrine did not release aspartate. These results support the hypothesis that endogenous aspartate in the rat RVLM is involved in the mediation of chemoreceptor reflexes.

2-Amino-5-phosphonovalerate↗
PubMed2002

Antinociceptive effect of cardiopulmonary chemoreceptor and baroreceptor reflex activation in the rat.

The effect on the nociceptive tail-flick (TF) reflex of cardiopulmonary chemoreceptor and arterial baroreceptor activation, producing Bezold-Jarisch like- and baro-reflex responses, respectively, was analysed in lightly halothane-anaesthetized rats. Intra-cardiac administration of phenylbiguanide (5-100 microg/kg, into the right atrium) or veratrine (30-150 microg/kg, into the left ventricle), which both elicited the characteristic Bezold-Jarisch-like cardiovascular reflex responses (hypotension and bradycardia), produced a dose-dependent increase in TF latency. A similar inhibitory influence on the TF reflex was noted upon baroreflex activation by acute administration of phenylephrine (15-50 microg/kg i.v.) or aortic depressor nerve stimulation (100-400 microA). As expected from the involvement of local excitatory amino acid receptors in both vagally mediated cardiovascular reflex responses and inhibition of the TF reflex, microinjections of kynurenic acid (3 nmol/0.1 microl), an N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonist, into the nucleus tractus solitarius, prevented the cardiovascular responses as well as the concomitant increase in TF latency produced by cardiopulmonary chemoreceptor and baroreceptor stimulations. The present data show that induction of the cardiopulmonary chemoreceptor and baroreceptor reflexes produces an antinociceptive effect which can be assessed using the TF test, and that glutamate ionotropic receptors within the nucleus tractus solitarius mediate this effect.

Analgesics↗
PubMed1986

Degenerative lesions of a coronary chemoreceptor and nearby neural elements in the hearts of victims of sudden death.

A coronary chemoreceptor and its neighboring nerves and ganglia were studied by serial section from the hearts of 11 victims of sudden unexpected death. Either focal or extensive inflammatory destruction was present in the chemoreceptors of 10 of the 11 hearts, and similar abnormalities of local nerves and ganglia were present in all 11 hearts. Because an identical coronary chemoreceptor in the dog has previously been shown to be the site of origin of a powerful reflex with major influence on the electrical activity of the heart, the functional significance of the neural abnormalities found in these 11 human hearts may include important distortion of cardiac rhythm, conduction or repolarization. Future studies are needed to determine the prevalence of such lesions in the hearts of other victims of sudden death and among control subjects, as well as to determine the etiology of this special neuropathology of the heart.

Adolescent↗
PubMed2003

Peripheral chemoreceptor activity in sleeping neonates exposed to warm environments.

In neonates, it is often assumed that ventilatory control and heat stress interact. Thus the two factors have been implicated in various pathologies (apnoea, sudden infant death syndrome). However, little is known about the mechanisms of this interaction, and the influence of sleep is still debated. This study aimed at determining the influence of warm exposure on the decrease in ventilation during a hyperoxic test (HT), which is considered to be a measure of peripheral chemoreceptor activity. The test was performed in active (AS) and quiet sleep (QS) in 12 neonates exposed to thermoneutral or warm environments. The HT consisted of 30 s of inspired, 100% O(2). The ventilatory response was assessed in terms of a response time, defined as the time elapsing between HT onset and the first significant change in V(E). Our results show that, in both thermal conditions, the fall in V(E) was higher in AS than in QS. Warm exposure significantly enhanced the ventilatory response in AS (-27.5 +/- 8.7% vs. -38.3 +/- 8.8%, P < 0.01) but not in QS. A thermometabolic drive or inputs from thermoreceptors could be involved in the reinforcement of peripheral chemoreceptor activity in AS in warmer environments, which could contribute to an increasing risk of apnoea in neonates with altered chemoreceptor function. Since hypothalamic structures are involved in thermoregulatory, sleep processes and (probably) in respiratory control, it could well be the principal site where this interaction occurs.

Body Temperature Regulation↗
PubMed2006

Tuning a bacterial chemoreceptor with protein-membrane interactions.

Chemoreceptors in Escherichia coli are homodimeric transmembrane proteins that convert environmental stimuli into intracellular signals controlling flagellar motion. Chemoeffectors bind to the extracellular (periplasmic) domain of the receptors, whereas their cytoplasmic domain mediates signaling and adaptation. The second transmembrane helix (TM2) connects these two domains. TM2 contains an aliphatic core flanked by amphipathic aromatic residues that have specific affinity for polar-hydrophobic membrane interfaces. We previously showed that Trp-209, near the cytoplasmic end of TM2, helps maintain the normal baseline-signaling state of the aspartate chemoreceptor (Tar) and that Tyr-210 plays an auxiliary role in this control. We have now repositioned the Trp-209/Tyr-210 pair in single-residue increments about the cytoplasmic polar-hydrophobic interface. Changes from WY-2 to WY+1 modulate the baseline-signaling state of the receptor in predictable and incremental steps that can be compensated by adaptive methylation/demethylation. Greater displacements, as in WY-3, WY+2, and WY+3, bias the receptor to the off kinase-inhibiting state or the on kinase-stimulating state, respectively, to a degree that cannot be fully compensated by the adaptation system. Aromatic residues analogous to Trp-209/Tyr-210 are present in other chemoreceptors and many transmembrane sensor kinases, where they may serve a similar function.

Amino Acid Sequence↗
PubMed1999

Adenosine inhibits L-type Ca2+ current and catecholamine release in the rabbit carotid body chemoreceptor cells.

In an in vitro preparation of the intact carotid body (CB) of the rabbit, adenosine (100 microM) inhibited hypoxia-induced catecholamine release by 25%. The specific A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 microM) prevented the inhibition and increased the response to hypoxia further. In isolated chemoreceptor cells from the same species, adenosine inhibited voltage-dependent Ca2+ currents by 29% at 1 microM (concentration producing half-maximal inhibition, IC50 = 50 nM). This inhibition was mimicked by R(-)N6-(2-phenylisopropyl)-adenosine and 2-chloroadenosine (1 microM), two purinergic agonists poorly active at the intracellular ('P') site, and persisted in the presence of dipyridamole (a blocker of adenosine uptake; 1 microM) and was fully inhibited by 8-phenyltheophylline (10 microM). The A1 antagonists DPCPX (10 microM) and 8-cyclopentyl-1,3-dimethylxantine (0.1 microM) inhibited the effect of adenosine by 93% (IC50 = 0.14 microM) and 59%, respectively. The inhibition of the Ca2+ current (I(Ca)) was reduced by nisoldipine (an L-type Ca2+ channel antagonist) by nearly 50%, and was unaltered by omega-conotoxin GVIA, a blocker of N-type Ca2+ channels. Adenosine did not affect the voltage-dependent Na+ current (I(Na)) or K+ current (I(K)). We conclude that adenosine A1 receptors are located in chemoreceptor cells and mediate the inhibition of L-type Ca2+ channels and thereby the release of catecholamines produced by hypoxia. The data also indicate that endogenous adenosine acts as a physiological negative modulator of the chemoreceptor cell function. The previously reported excitatory action of adenosine on the activity of the sensory nerve of the CB is discussed in terms of a balance between the inhibition mediated by A1 receptors and the excitation mediated by A2 receptors.

Adenosine↗
PubMed2001

Obstructive sleep apnea and hypertension: are peripheral chemoreceptors involved?

The mechanism of pathogenesis of hypertension in patients with obstructive sleep apnea (OSA) is unknown. Many investigators point to the high sympathetic nervous system activity (SNS) observed in OSA patients. However, there is no clear explanation as to the mechanism for the development of SNS hyperactivity in these patients. A common feature of patients with OSA is repetitive bouts of transient hypoxemia during sleep. Repetitive transient hypoxemia in rats has resulted in hypertension. In OSA patients, resolution of nocturnal hypoxemia with CPAP has corrected nocturnal and diurnal hypertension. Also, exposure to hyperoxia reduces blood pressure and sympathetic activity in OSA patients, but not in normals. These data suggest a significant role of peripheral chemoreceptors in the regulation of vascular tone. We hypothesize that peripheral chemoreceptors significantly contribute to the pathogenesis of hypertension in patients with OSA and that this is associated with chemoreceptor hyperactivity. This implies that correcting the intermittent nocturnal hypoxemia alone may prevent the cardiovascular morbidity associated with obstructive sleep apnea.

Animals↗
PubMed2002

Collaborative signaling by mixed chemoreceptor teams in Escherichia coli.

Chemoreceptors of the methyl-accepting chemotaxis protein family form clusters, typically at the cell pole(s), in both Bacteria and Archaea. To elucidate the architecture and signaling role of receptor clusters, we investigated interactions between the serine (Tsr) and aspartate (Tar) chemoreceptors in Escherichia coli by constructing Tsr mutations at the six hydrophobic and five polar residues implicated in "trimer of dimers" formation. Tsr mutants with proline replacements could not mediate serine chemotaxis, receptor clustering, or clockwise flagellar rotation. Alanine and tryptophan mutants, although also nonchemotactic, formed receptor clusters, and some produced clockwise flagellar rotation, indicating receptor-coupled activation of the signaling CheA kinase. The alanine and tryptophan mutants evidently assemble defective receptor complexes that cannot modulate CheA activity in response to serine stimuli. In cells containing wild-type Tar receptors, tryptophan replacements in Tsr interfered with Tar function, whereas four Tsr mutants with alanine replacements regained Tsr function. These epistatic and rescuable phenotypes imply interactions between Tsr and Tar dimers in higher-order signaling teams. The bulky side chain in tryptophan mutants may prevent stimulus-induced conformational changes in the team, whereas the small side chain in alanine mutants may permit signaling control when teamed with functional receptor molecules. Direct physical interactions between Tsr and Tar molecules were observed by in vivo chemical crosslinking. Wild-type Tsr crosslinked to Tar, whereas a clustering-defective proline replacement mutant did not. These findings indicate that bacterial chemoreceptor clusters are comprised of signaling teams, seemingly based on trimers of dimers, that can contain different receptor types acting collaboratively.

Bacterial Proteins↗
PubMed1999

Efficient adaptational demethylation of chemoreceptors requires the same enzyme-docking site as efficient methylation.

The mechanistic basis of sensory adaptation and gradient sensing in bacterial chemotaxis is reversible covalent modification of transmembrane chemoreceptors, methylation, and demethylation at specific glutamyl residues in their cytoplasmic domains. These reactions are catalyzed by a dedicated methyltransferase CheR and a dedicated methylesterase CheB. The esterase is also a deamidase that creates certain methyl-accepting glutamyls by hydrolysis of glutamine side chains. We investigated the action of CheB and its activated form, phospho-CheB, on a truncated form of the aspartate receptor of Escherichia coli that was missing the last 5 aa of the intact receptor. The deleted pentapeptide is conserved in several chemoreceptors in enteric and related bacteria. The truncated receptor was much less efficiently demethylated and deamidated than intact receptor, but essentially was unperturbed for kinase activation or transmembrane signaling. CheB bound specifically to an affinity column carrying the isolated pentapeptide, implying that in the intact receptor the pentapeptide serves as a docking site for the methylesterase/deamidase and that the truncated receptor was inefficiently modified because the enzyme could not dock. It is striking that the same pentapeptide serves as an activity-enhancing docking site for the methyltransferase CheR, the other enzyme involved in adaptational covalent modification of chemoreceptors. A shared docking site raises the tantalizing possibility that relative rates of methylation and demethylation could be influenced by competition between the two enzymes at that site.

Bacterial Proteins↗
PubMed2001

Sensing of cytoplasmic pH by bacterial chemoreceptors involves the linker region that connects the membrane-spanning and the signal-modulating helices.

The two major chemoreceptors of Escherichia coli, Tsr and Tar, mediate opposite responses to the same changes in cytoplasmic pH (pH(i)). We set out to identify residues involved in pH(i) sensing to gain insight into the general mechanisms of signaling employed by the chemoreceptors. Characterization of various chimeras of Tsr and Tar localized the pH(i)-sensing region to Arg(259)-His(267) of Tar and Gly(261)-Asp(269) of Tsr. This region of Tar contains three charged residues (Arg(259)-Ser(261), Asp(263), and His(267)) that have counterparts of opposite charge in Tsr (Gly(261)-Glu(262), Arg(265), and Asp(269)). The replacement of all of the three charged residues in Tar or Arg(259)-Ser(260) alone by the corresponding residues of Tsr reversed the polarity of pH(i) response, whereas the replacement of Asp(263) or His(267) did not change the polarity but altered the time course of pH(i) response. These results suggest that the electrostatic properties of a short cytoplasmic region within the linker region that connects the second transmembrane helix to the first methylation helix is critical for switching the signaling state of the chemoreceptors during pH sensing. Similar conformational changes of this region in response to external ligands may be critical components of transmembrane signaling.

Amino Acid Sequence↗
PubMed2002

Dual recognition of the bacterial chemoreceptor by chemotaxis-specific domains of the CheR methyltransferase.

Adaptation to persisting stimulation is required for highly sensitive detection of temporal changes of stimuli, and often involves covalent modification of receptors. Therefore, it is of vital importance to understand how a receptor and its cognate modifying enzyme(s) modulate each other through specific protein-protein interactions. In the chemotaxis of Escherichia coli, adaptation requires methylation of chemoreceptors (e.g. Tar) catalyzed by the CheR methyltransferase. CheR binds to the C-terminal NWETF sequence of a chemoreceptor that is distinct from the methylation sites. However, little is known about how CheR recognizes its methylation sites or how it is distributed in a cell. In this study, we used comparative genomics to demonstrate that the CheR chemotaxis methyltransferase contains three structurally and functionally distinct modules: (i) the catalytic domain common to a methyltransferase superfamily; (ii) the N-terminal domain; and (iii) the beta-subdomain of the catalytic domain, both of which are found exclusively in chemotaxis methyltransferases. The only evolutionary conserved motif specific to CheR is the positively charged face of helix alpha2 in the N-terminal domain. The disulfide cross-linking analysis suggested that this face interacts with the methylation helix of Tar. We also demonstrated that CheR localizes to receptor clusters at cell poles via interaction of the beta-subdomain with the NWETF sequence. Thus, the two chemotaxis-specific modules of CheR interact with distinct regions of the chemoreceptor for targeting to the receptor cluster and for recognition of the substrate sites, respectively.

Amino Acid Sequence↗