Redefining the components of central CO₂ chemosensitivity – towards a better understanding of mechanism

Abstract

The field of CO2 chemosensitivity has developed considerably in recent years. There has been a mounting number of competing nuclei proposed as chemosensitive along with an ever increasing list of potential chemosensory transducing molecules. Is it really possible that all of these areas and candidate molecules are involved in the detection of chemosensory stimuli? How do we discriminate rigorously between molecules that are chemosensory transducers at the head of a physiological reflexversusthose that just happen to display sensitivity to a chemosensory stimulus? Equally, how do we differentiate between nuclei that have a primary chemosensory function, versusthose that are relays in the pathway? We have approached these questions by proposing rigorous definitions for the different components of the chemosensory reflex, going from the salient molecules and ions, through the components of transduction to the identity of chemosensitive cells and chemosensitive nuclei. Our definitions include practical and rigorous experimental tests that can be used to establish the identity of these components. We begin by describing the need for central CO2 chemosensitivity and the problems that the field has faced. By comparing chemosensory mechanisms to those in the visual system we suggest stricter definitions for the components of the chemosensory pathway. We then, considering these definitions, re-evaluate current knowledge of chemosensory transduction, and propose the ‘multiple salient signal hypothesis’ as a framework for understanding the multiplicity of transduction mechanisms and brain areas seemingly involved in chemosensitivity.

Effect of temperature on chemosensitive locus coeruleus neurons of Savannah monitor lizardsVaranus exanthematicus

“…In addition, in bullfrogs, increases and decreases in temperature influence the magnitude of the chemosensitive response; however, the CI in monitor lizards was not temperature dependent. Therefore, our study shows that in V. exanthematicus, despite fewer LC neurons being activated by HA, a higher proportion of the LC neurons responded by decreasing their firing rates during exposure to high CO 2 (7-10% CO 2 ) at 20°C (37%) -a response that was no longer exhibited at a higher temperature (30°C (Guyenet and Bayliss, 2015;Huckstepp and Dale, 2011;Nattie, 1999). Studies investigating central respiratory chemoreceptors have focused mainly on neurons that are excited by HA, because some of the most studied chemosensitive areas like the nucleus tractus solitarius (NTS), retrotrapezoid nucleus (RTN) and the LC have a high percentage of HA-responsive neurons that are activated by CO 2 (Conrad et al, 2009;Mulkey et al, 2004;Nichols et al, 2009;Ritucci et al, 2005); however, CO 2 -inhibited neurons also possibly play a role in the ventilatory control network in mammals (Iceman et al, 2014;Wang et al, 1998;Wang and Richerson, 1999).…”

“…The negative feedback system that drives ventilation has been mainly elucidated in mammals that tightly regulate arterial pH. Specifically, chemosensory structures are well defined and the cellular mechanisms underlying chemosensitivity have been extensively studied in mammals (Guyenet and Bayliss, 2015;Hartzler and Putnam, 2009;Huckstepp and Dale, 2011), where the CO 2 /pH-sensitive brainstem areas involved in respiratory chemosensing are located in regions surrounding the fourth ventricle (Coates et al, 1993;Huckstepp and Dale, 2011).…”

Modulation of sensory information processing by a neuroglobin in Caenorhabditis elegans

“…Studies of O 2 sensing in the glomus cells of the carotid bodies of mammals have implicated multiple O 2 -sensing mechanisms that could act together to sculpt O 2 response features (4). Similarly, a range of CO 2 /pH-responsive molecules have been identified in mammals, although whether any of the numerous CO 2 /pH-responsive cells use a combination of transducers is unclear (24).…”

Environmental CO 2 inhibits Caenorhabditis elegans egg-laying by modulating olfactory neurons and evokes widespread changes in neural activity

“…Peripheral sensors in the carotid bodies and incompletely defined central chemoreceptors respond to small changes in CO 2 /H + by homeostatically altering the breathing rate (3,20). In concert, pH and HCO 3 − sensors in the kidneys regulate H + and HCO 3 − excretion (21, 22).…”

“…pH changes can modulate G protein-coupled receptors (7), Ca 2+ -activated K + channels (8), inwardly rectifying K + channels (9), two pore domain K + channels (10), transient receptor potential (TRP) channels (11,12), acid-sensing ion channels (ASICs) (13,14), and Pyk2 and ErbB1/2 kinases (15). HCO 3 − modulates soluble adenylate cyclase (16) and transmembrane guanylate cyclases (17); and CO 2 (aq) has been proposed to regulate transmembrane guanylate cyclases (18) and connexin 26 (19) directly. Cells expressing any of these proteins potentially could transduce changes in CO 2 /H + , raising the question: Do animals use a few specific sensory channels or a large distributed set to respond to ecologically meaningful fluctuations in CO 2 ?…”