Central chemosensitivity and the reaction theory.

Loeschcke, H. H.

doi:10.1113/jphysiol.1982.sp014397

Cited by 326 publications

(241 citation statements)

References 55 publications

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“…The 'distributed chemoreception theory' states that the exquisite CO 2 sensitivity of the respiratory network results from the summation of the lesser sensitivities of its parts (Feldman et al 2003). Conversely, the 'specialized chemoreceptor theory' (Guyenet 2008) originated from the work of Loeschcke and Mitchell (Loeschcke 1982), who favoured dedicated sites for CO 2 sensing restricted to discrete regions of the ventral medullary surface. The two best-documented candidates for the latter role are raphe serotonergic nuclei (Richerson 2004) and the retrotrapezoid nucleus (RTN), a group of glutamatergic neurons located in the marginal layer of the VLM beneath the facial motor nucleus (Mulkey et al 2004).…”

Section: Mutations In Phox2b and The Drive To Breathementioning

confidence: 99%

Breathing withPhox2b

Dubreuil

Barhanin

Goridis

et al. 2009

Phil. Trans. R. Soc. B

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In the last few years, elucidation of the architecture of breathing control centres has reached the cellular level. This has been facilitated by increasing knowledge of the molecular signatures of various classes of hindbrain neurons. Here, we review the advances achieved by studying the homeodomain factor Phox2b, a transcriptional determinant of neuronal identity in the central and peripheral nervous systems. Evidence from human genetics, neurophysiology and mouse reverse genetics converges to implicate a small population of Phox2b-dependent neurons, located in the retrotrapezoid nucleus, in the detection of CO 2 , which is a paramount source of the 'drive to breathe'. Moreover, the same and other studies suggest that an overlapping or identical neuronal population, the parafacial respiratory group, might contribute to the respiratory rhythm at least in some circumstances, such as for the initiation of breathing following birth. Together with the previously established Phox2b dependency of other respiratory neurons (which we review briefly here), our new data highlight a key role of this transcription factor in setting up the circuits for breathing automaticity.

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Section: Mutations In Phox2b and The Drive To Breathementioning

confidence: 99%

Breathing withPhox2b

Dubreuil

Barhanin

Goridis

et al. 2009

Phil. Trans. R. Soc. B

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“…Studies of arterial pH, pHi, pHe, and neuronal activity indicate that changes in pHi are a sufficient stimulus of central chemosensory neurons (Filosa et al, 2002;Wang et al, 2002;Putnam et al, 2004) but not a necessary stimulus. In addition, many of the putative ion channels (Putnam et al, 2004;Chernov et al, 2008) and neurotransmitter receptors (Loeschcke, 1982) thought to mediate chemosensitivity are sensitive to changes in pHe, rather than pHi. Our measurements strongly suggest that pHe is also a sufficient stimulus of central chemosensors, because ventilation was increased when pHe decreased, although it seems likely that 4-CIN treatment alkalinized neuronal pHi.…”

Section: Implications For Ventilatory Central Chemosensitivitymentioning

confidence: 99%

Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

Erlichman¹,

Hewitt²,

Damon³

et al. 2008

J. Neurosci.

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The astrocyte-neuronal lactate-shuttle hypothesis posits that lactate released from astrocytes into the extracellular space is metabolized by neurons. The lactate released should alter extracellular pH (pHe), and changes in pH in central chemosensory regions of the brainstem stimulate ventilation. Therefore, we assessed the impact of disrupting the lactate shuttle by administering 100 M ␣-cyano-4-hydroxycinnamate (4-CIN), a dose that blocks the neuronal monocarboxylate transporter (MCT) 2 but not the astrocytic MCTs (MCT1 and MCT4). Administration of 4-CIN focally in the retrotrapezoid nucleus (RTN), a medullary central chemosensory nucleus, increased ventilation and decreased pHe in intact animals. In medullary brain slices, 4-CIN reduced astrocytic intracellular pH (pHi) slightly but alkalinized neuronal pHi. Nonetheless, pHi fell significantly in both cell types when they were treated with exogenous lactate, although 100 M 4-CIN significantly reduced the magnitude of the acidosis in neurons but not astrocytes. Finally, 4-CIN treatment increased the uptake of a fluorescent 2-deoxy-D-glucose analog in neurons but did not alter the uptake rate of this 2-deoxy-D-glucose analog in astrocytes. These data confirm the existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN, and lactate derived from astrocytes forms part of the central chemosensory stimulus for ventilation in this nucleus. When the lactate shuttle was disrupted by treatment with 4-CIN, neurons increased the uptake of glucose. Therefore, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates.

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“…Both peripheral and central chemosensors measure PCO 2 and cause adaptive changes in breathing to closely regulate its level. The predominant theory of chemoreception ("reaction theory") put forward by Winterstein and Loeschcke proposes that PCO 2 is measured only via consequent changes in pH [39,40]. However, other molecules could potentially signal changes in PCO 2 -CO 2 itself and HCO 3 − , and these alternatives have rather been neglected.…”

Section: Co 2 Chemosensory Transductionmentioning

confidence: 99%

Measurement of purine release with microelectrode biosensors

Dale

Frenguelli

2011

Purinergic Signalling

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Purinergic signalling departs from traditional paradigms of neurotransmission in the variety of release mechanisms and routes of production of extracellular ATP and adenosine. Direct real-time measurements of these purinergic agents have been of great value in understanding the functional roles of this signalling system in a number of diverse contexts. Here, we review the methods for measuring purine release, introduce the concept of microelectrode biosensors for ATP and adenosine and explain how these have been used to provide new mechanistic insight in respiratory chemoreception, synaptic physiology, eye development and purine salvage. We finish by considering the association of purine release with pathological conditions and examine the possibilities that biosensors for purines may one day be a standard part of the clinical diagnostic tool chest.Keywords Biosensor . Real-time measurement . Epilepsy . Stroke . Chemosensory mechanisms . DevelopmentThe need for real-time purine measurementThe traditional paradigm of synaptic transmission involves exocytotic release of transmitter from a defined presynaptic structure into the narrow gap of the synaptic cleft where it diffuses to activate receptors on the closely apposed postsynaptic membrane. Release is time-locked to the presynaptic action potential and results in the predictable occurrence of postsynaptic events on defined time scales. While capturing the essence of synaptic transmission, this paradigm is an oversimplification. For example, transmitters such as GABA [1] and glutamate [2] can spill out of the synaptic cleft to have more diffuse and widespread actions than this classical model suggests. Under pathological conditions, transmitters and neurotransmitters, such as glutamate [3], can be released by the reversal of Na + -dependent concentrative transporters.The purines, ATP and adenosine, depart from this paradigm even more comprehensively. ATP can indeed be released at synapses [4,5]. However, in the CNS, it seems that it acts mainly as a cotransmitter [6,7], and there are very few synapses where it acts as the principal transmitter. ATP is also released by glial cells [8,9] for the most part via exocytosis [10,11] but see [12]. However, ATP can also be released via a variety of channel-mediated mechanisms (for example, via gap junction hemichannels [13][14][15] and volume-activated channels [16,17]). Receptors for ATP are widespread throughout the CNS; yet, the cellular sources of ATP release to activate these receptors are not immediately obvious. In addition, although ATP can be broken down to ADP and further to adenosine, these breakdown products are themselves active at particular receptor subtypes.The routes for adenosine release and the cellular sources seem to be even more mysterious than those for ATP. For example, there is abundant evidence that adenosine can arise from the breakdown of previously released ATP [18].

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Central chemosensitivity and the reaction theory.

Cited by 326 publications

References 55 publications

Breathing withPhox2b

Breathing withPhox2b

Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

Measurement of purine release with microelectrode biosensors

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