{"title":"Olfactory CO2 chemoreceptors","authors":"E.Lee Coates","doi":"10.1016/S0034-5687(01)00292-4","DOIUrl":"10.1016/S0034-5687(01)00292-4","url":null,"abstract":"<div><p>Amphibians and reptiles possess CO<sub>2</sub>-sensitive olfactory receptors that cause a dose-dependent decrease in breathing when stimulated by CO<sub>2</sub> concentrations ranging from 0.5 to 8%. In amphibians, it has been shown that inhibition of the enzyme, carbonic anhydrase (CA), attenuates the response of CO<sub>2</sub>-sensitive olfactory receptors to transient changes in nasal CO<sub>2</sub>. Histology and electrophysiology studies in frogs show that identification of sites of CA activity can serve as markers for locations of CO<sub>2</sub> chemosensitivity in the olfactory epithelium. There is also growing evidence that CO<sub>2</sub> receptors may be present in the olfactory epithelium of mammals. The objectives of this review are to, (1) summarize the current state of knowledge of olfactory CO<sub>2</sub> receptors in amphibians, reptiles, and mammals; (2) present results from an experiment designed to determine the distribution and density of CA activity within the rat nasal cavity; (3) show results from an experiment that recorded the olfactory receptor response to CO<sub>2</sub> in areas of the rat nasal cavity exhibiting the highest densities of CA activity; and (4) discuss the presumed role of the olfactory CO<sub>2</sub> receptors in the control of breathing and in abnormalities of breathing, such as sudden infant death syndrome (SIDS).</p></div>","PeriodicalId":20976,"journal":{"name":"Respiration physiology","volume":"129 1","pages":"Pages 219-229"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0034-5687(01)00292-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75961525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Respiratory plasticity: differential actions of continuous and episodic hypoxia and hypercapnia","authors":"T.L Baker , D.D Fuller , A.G Zabka , G.S Mitchell","doi":"10.1016/S0034-5687(01)00280-8","DOIUrl":"10.1016/S0034-5687(01)00280-8","url":null,"abstract":"<div><p>The objectives of this paper are: (1) to review advances in our understanding of the mechanisms of respiratory plasticity elicited by episodic versus continuous hypoxia in short to intermediate time domains (min to h); and (2) to present new data suggesting that different patterns of hypercapnia also elicit distinct forms of respiratory plasticity. Episodic, but not continuous hypoxia elicits long-term facilitation (LTF) of respiratory motor output. Phrenic LTF is a serotonin-dependent central neural mechanism that requires: (a) activation of spinal serotonin receptors; and (b) spinal protein synthesis. Continuous and episodic hypercapnia also elicit different mechanisms of plasticity. Continuous, severe hypercapnia (25 min of ∼10% inspired CO<sub>2</sub>) elicits long-term depression (LTD) of phrenic motor output (−33±8% at 60 min post-hypercapnia) in anesthetized rats. In contrast, 3,<!--> <!-->5 min hypercapnic episodes do not elicit LTD (9±17% at 60 min). We hypothesize that the response of respiratory motoneurons to serotonergic and noradrenergic modulation may contribute to pattern sensitivity to hypoxia and hypercapnia.</p></div>","PeriodicalId":20976,"journal":{"name":"Respiration physiology","volume":"129 1","pages":"Pages 25-35"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0034-5687(01)00280-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91271759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ventrolateral neurons of medullary organotypic cultures: intracellular pH regulation and bioelectric activity","authors":"Martin Wiemann, Dieter Bingmann","doi":"10.1016/S0034-5687(01)00282-1","DOIUrl":"10.1016/S0034-5687(01)00282-1","url":null,"abstract":"<div><p>The hypothesized role of the intracellular pH (pH<sub>i</sub>) as a proximate stimulus for central chemosensitive neurons is reviewed on the basis of data obtained from organotypic cultures of the medulla oblongata (obex level) of new born rats (OMC). Within OMC a subset of neurons responds to hypercapnia as do neurons in the same (or similar) brain areas in vivo. Maneuvers altering intra- and/or extracellular pH (pH<sub>o</sub>) such as hypercapnia, bicarbonate-withdrawal, or ammonium pre-pulses, evoked well defined changes of the neuronal pH<sub>i</sub>. During hypercapnia (pH<sub>o</sub> 7.0) or bicarbonate-withdrawal (pH<sub>o</sub> 7.4) most ventrolateral neurons adopted a pH<sub>i</sub> which was ≤0.2 pH units below the steady state pH<sub>i</sub>, while signs of pH<sub>i</sub>-regulation occurred only in a small fraction of neurons. During all treatments leading to intracellular acidosis, bioelectric activity of chemosensitive neurons increased and was often indistinguishable from the response to hypercapnia, regardless of whether pH<sub>o</sub> was unchanged, decreased or increased during the treatment. These data strongly suggest that the pH<sub>i</sub> acts as proximate stimulus. The mode of acid extrusion of chemosensitive neurons is, therefore, of major importance for the control of central chemosensitivity. Immunocytochemical data, pH<sub>i</sub> measurements and neuropharmacological studies with novel drugs pointed to the Na<sup>+</sup>/H<sup>+</sup> exchanger subtype 3 (NHE3) as a main acid extruder in ventrolateral chemosensitive neurons. Possible functions and neuropharmacological strategies arising from this very local NHE3 expression are discussed.</p></div>","PeriodicalId":20976,"journal":{"name":"Respiration physiology","volume":"129 1","pages":"Pages 57-70"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0034-5687(01)00282-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82129786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cytoarchitecture of central chemoreceptors in the mammalian ventral medulla","authors":"Yasumasa Okada , Zibin Chen , Shun-ichi Kuwana","doi":"10.1016/S0034-5687(01)00279-1","DOIUrl":"10.1016/S0034-5687(01)00279-1","url":null,"abstract":"<div><p>We reviewed the previous reports on the fine anatomy of the mammalian ventral medulla with special attention to the cytoarchitecture of the superficial chemosensitive regions to summarize what is known, what is not yet known, and what should be studied in the future. We also reviewed studies on anatomical relationship between neurons and vessels, and morphological studies on dendrites of respiratory or chemosensitive neurons. When we compared the morphological reports on the ventral and dorsal putative chemosensitive regions, similarities were found as follows. Chemosensitive cells were often found not only near the ventral surface but near the dorsal surface of the brainstem. Dendritic projection towards the surface was a common characteristic in the ventral and dorsal chemosensitive neurons. Morphological abnormality in the brainstem of sudden infant death syndrome victims was also summarized. On the basis of the previous reports we discussed the perspective on the future study on central chemoreception. Among various unanswered questions in central chemosensitivity studies, physiological significance of surface cells and surface extending dendrites is the most important topic, and must be thoroughly investigated.</p></div>","PeriodicalId":20976,"journal":{"name":"Respiration physiology","volume":"129 1","pages":"Pages 13-23"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0034-5687(01)00279-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83416754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Intracellular pH regulation of neurons in chemosensitive and nonchemosensitive areas of brain slices","authors":"Robert W Putnam","doi":"10.1016/S0034-5687(01)00281-X","DOIUrl":"10.1016/S0034-5687(01)00281-X","url":null,"abstract":"<div><p>The role of changes of intracellular pH (pH<sub>i</sub>) as the proximal signal in central chemosensitive neurons has been studied. pH<sub>i</sub> recovery from acidification is mediated by Na<sup>+</sup>/H<sup>+</sup> exchange in all medullary neurons and pH<sub>i</sub> recovery from alkalinization is mediated by Cl<sup>−</sup>/HCO<sub>3</sub><sup>−</sup> exchange in most medullary neurons. These exchangers are more sensitive to inhibition by changes in extracellular pH (pH<sub>o</sub>) in neurons from chemosensitive regions compared to those from nonchemosensitive regions. Thus, neurons from chemosensitive regions exhibit a maintained intracellular acidification in response to hypercapnic acidosis but they show pH<sub>i</sub> recovery in response to isohydric hypercapnia. A similar pattern of pH<sub>i</sub> response is seen in other CO<sub>2</sub>/H<sup>+</sup>-responsive cells, including glomus cells, sour taste receptor cells, and chemosensitive neurons from snails, suggesting that a maintained fall of pH<sub>i</sub> is a common feature of the proximal signal in all CO<sub>2</sub>/H<sup>+</sup>-sensitive cells. To further evaluate the potential role of pH<sub>i</sub> changes as proximal signals for chemosensitive neurons, studies must be done to: determine why a lack of pH<sub>i</sub> recovery from hypercapnic acidosis is seen in some nonchemosensitive neurons; establish a correlation between hypercapnia-induced changes of pH<sub>i</sub> and membrane potential (V<sub>m</sub>); compare the hypercapnia-induced pH<sub>i</sub> changes seen in neuronal cell bodies with those in dendritic processes; understand why the V<sub>m</sub> response to hypercapnia of many chemosensitive neurons is washed out when using whole cell patch pipettes; and employ knock out mice to investigate the role of certain proteins in the CO<sub>2</sub>/H<sup>+</sup> response of chemosensitive neurons.</p></div>","PeriodicalId":20976,"journal":{"name":"Respiration physiology","volume":"129 1","pages":"Pages 37-56"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0034-5687(01)00281-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75306630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An alternative approach to the identification of respiratory central chemoreceptors in the brainstem","authors":"Chun Jiang, Haoxing Xu, Ningren Cui, Jianping Wu","doi":"10.1016/S0034-5687(01)00301-2","DOIUrl":"10.1016/S0034-5687(01)00301-2","url":null,"abstract":"<div><p>Central chemoreceptors (CCRs) play a crucial role in autonomic respiration. Although a variety of brainstem neurons are CO<sub>2</sub> sensitive, it remains to know which of them are the CCRs. In this article, we discuss a potential alternative approach that may allow an access to the CCRs. This approach is based on identification of specific molecules that are CO<sub>2</sub> or pH sensitive, exist in brainstem neurons, and regulate cellular excitability. Their molecular identity may provide another measure in addition to the electrophysiologic criteria to indicate the CCRs. The inward rectifier K<sup>+</sup> channels (Kir) seem to be some of the CO<sub>2</sub> sensing molecules, as they regulate membrane potential and cell excitability and are pH sensitive. Among homomeric Kirs, we have found that even the most sensitive Kir1.1 and Kir2.3 have pK∼6.8, suggesting that they may not be capable of detecting hypocapnia. We have studied their biophysical properties, and identified a number of amino acid residues and molecular motifs critical for the CO<sub>2</sub> sensing. By comparing all Kirs using the motifs, we found the same amino acid sequence in Kir5.1, and demonstrated the pH sensitivity in heteromeric Kir4.1 and Kir5.1 channels to be pK∼7.4. In current clamp, we show evidence that the Kir4.1–Kir5.1 can detect P<sub>CO<sub>2</sub></sub> changes in either hypercapnic or hypocapnic direction. Our in-situ hybridization studies have indicated that they are coexpressed in brainstem cardio–respiratory nuclei. Thus, it is likely that the heteromeric Kir4.1–Kir5.1 contributes to the CO<sub>2</sub>/pH sensitivity in these neurons. We believe that this line of research intended to identify CO<sub>2</sub> sensing molecules is an important addition to current studies on the CCRs.</p></div>","PeriodicalId":20976,"journal":{"name":"Respiration physiology","volume":"129 1","pages":"Pages 141-157"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0034-5687(01)00301-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87965458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M Andrzejewski, K Mückenhoff, P Scheid, D Ballantyne
{"title":"Synchronized rhythms in chemosensitive neurons of the locus coeruleus in the absence of chemical synaptic transmission","authors":"M Andrzejewski, K Mückenhoff, P Scheid, D Ballantyne","doi":"10.1016/S0034-5687(01)00300-0","DOIUrl":"10.1016/S0034-5687(01)00300-0","url":null,"abstract":"<div><p>The activity of locus coeruleus (LC) neurons was examined in the en bloc isolated brainstem–spinal cord of the neonatal rat using paired whole cell or whole cell plus extracellular recording. In artificial cerebrospinal fluid (ACSF) LC neurons were synchronized by their respiratory innervation and in some neurons showing tonic or burst patterns of discharge these patterns of discharge could also be synchronized. Replacing ACSF with low Ca<sup>2+</sup>-high Mg<sup>2+</sup> generated synchronized rhythmic bursts which remained synchronized at high CO<sub>2</sub> (up to 20%). This rhythm was suppressed by TTX. Substitution of Ba<sup>2+</sup> for Ca<sup>2+</sup> in ACSF generated a synchronized rhythm which was TTX-insensitive<strong>.</strong> The frequency of this rhythm increased by 31±16% on raising CO<sub>2</sub> concentration from 2 to 10%. We conclude that the capacity of chemosensitive LC neurons to generate a synchronized rhythm depends on their electrical coupling, but not on chemical synaptic transmission.</p></div>","PeriodicalId":20976,"journal":{"name":"Respiration physiology","volume":"129 1","pages":"Pages 123-140"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0034-5687(01)00300-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76026745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Douglas A Bayliss, Edmund M Talley, Jay E Sirois, Qiubo Lei
{"title":"TASK-1 is a highly modulated pH-sensitive ‘leak’ K+ channel expressed in brainstem respiratory neurons","authors":"Douglas A Bayliss, Edmund M Talley, Jay E Sirois, Qiubo Lei","doi":"10.1016/S0034-5687(01)00288-2","DOIUrl":"10.1016/S0034-5687(01)00288-2","url":null,"abstract":"<div><p>Central respiratory chemoreceptors adjust respiratory drive in a homeostatic response to alterations in brain pH and/or P<sub>CO<sub>2</sub></sub>. Multiple brainstem sites are proposed as neural substrates for central chemoreception, but molecular substrates that underlie chemosensitivity in respiratory neurons have not been identified. In rat brainstem neurons expressing transcripts for TASK-1, a two-pore domain K<sup>+</sup> channel, we characterized K<sup>+</sup> currents with kinetic and voltage-dependent properties identical to cloned rat TASK-1 currents. Native currents were sensitive to acid and alkaline shifts in the same physiological pH range as TASK-1 (pK∼7.4), and native and cloned pH-sensitive currents were modulated similarly by neurotransmitters and inhalational anesthetics. This pH-sensitive TASK-1 channel is an attractive candidate to mediate chemoreception because it is functionally expressed in respiratory-related neurons, including airway motoneurons and putative chemoreceptor neurons of locus coeruleus (LC). Inhibition of TASK-1 channels by extracellular acidosis can depolarize and increase excitability in those cells, thereby contributing to chemoreceptor function in LC neurons and directly enhancing respiratory motoneuronal output.</p></div>","PeriodicalId":20976,"journal":{"name":"Respiration physiology","volume":"129 1","pages":"Pages 159-174"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0034-5687(01)00288-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81119324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cell–cell coupling in CO2/H+-excited neurons in brainstem slices","authors":"Jay B Dean, Elizabeth A Kinkade, Robert W Putnam","doi":"10.1016/S0034-5687(01)00284-5","DOIUrl":"10.1016/S0034-5687(01)00284-5","url":null,"abstract":"<div><p>The indirect and direct electrical and anatomical evidence for the hypothesis that central chemoreceptor neurons in the dorsal brainstem (solitary complex, SC; locus coeruleus, LC) are coupled by gap junctions, as reported primarily in rat brainstem slices, and the methods used to study gap junctions in brain slices, are critiqued and reviewed. Gap junctions allow intercellular communication that could be important in either electrical coupling (intercellular flow of ionic current), metabolic coupling (intercellular flow of signaling molecules), or both, ultimately influencing excitability within the SC and LC during respiratory acidosis. Gap junctions may also provide a mechanism for modulating neuronal activity in the network under conditions that lead to increased or decreased central respiratory chemosensitivity. Indirect measures of electrical coupling suggest that junctional conductance between chemosensitive neurons is relatively insensitive to a broad range of intracellular pH (pH<sub>i</sub>), ranging from pH<sub>i</sub> ≈7.49 to ≈6.71 at 35–37 °C. In contrast, further reductions in pH<sub>i</sub>, down through pH<sub>i</sub> ≈6.67, abolish indirect measures of electrical coupling.</p></div>","PeriodicalId":20976,"journal":{"name":"Respiration physiology","volume":"129 1","pages":"Pages 83-100"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0034-5687(01)00284-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89903592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}