Re: Retrotrapezoid nucleus: a litmus test for the identification of central chemoreceptors

Abstract

Central chemoreception is the mechanism by which arterial blood P(CO2) is detected by the CNS to regulate breathing. Two main theories have been proposed to account for the phenomenon. The distributed chemosensitivity theory argues that pH sensitivity is a widespread attribute of brainstem neurones and that central chemoreception results from the cumulative effects of pH on countless neurones. The specialized chemoreceptor theory envisions the existence of small and specialized populations of CNS cells (chemoreceptors) that are unique in their ability to detect very small pH fluctuations and, via specific connections, regulate a respiratory network that is itself unresponsive to pH. The recently identified CO2-sensitive neurones of the retrotrapezoid nucleus (RTN) seem to possess most of the attributes that one would expect of such chemoreceptors. In this review we also suggest that many fewer medullary neurones are intrinsically responsive to CO2 in vivo than might have been anticipated from prior experimentation in vitro. The properties of RTN neurones provide renewed support for the specialized chemoreceptor theory of central chemoreception, proposed in the early 1960s. However, many uncertainties remain, especially as regards the molecular mechanisms of chemoreception, the type of cell that actually detects pH in vivo (neurone, glia or others) and the number and location of bona fide central chemoreceptors.

Role of chemoreceptors in mediating dyspnea

“…The hypothesis that 5-HT neurons are central CO 2 chemoreceptors has recently been challenged (Guyenet et al, 2005, 2008; Richerson et al, 2005; Richerson, 2005), in part based on data that suggests that TASK channels are responsible for chemosensitivity of 5-HT neurons, and that mice with genetic deletion of TASK channels have a normal ventilatory response to CO 2 (Mulkey et al, 2007b; Guyenet et al, 2008). However, the in vitro recordings reported by Mulkey et al (2007b) were from immature (7–12 day old) 5-HT neurons, and their responses were induced by a pathologically large decrease in pH (to 6.9).…”

In Transgenic Erythropoietin Deficient Mice, an Increase in Respiratory Response to Hypercapnia Parallels Abnormal Distribution of CO2/H+-Activated Cells in the Medulla Oblongata

“…These observations can be related to the presence of EpoR in the main peripheral and central respiratory areas that regulate breathing ( Soliz et al, 2005 ). On the basis of these data, and keeping in mind that the CO 2 /H + regulation of breathing mainly depends on brainstem structures ( Feldman et al, 2003 ; Guyenet et al, 2005 , 2019 ; Nattie and Li, 2006a ; Guyenet and Bayliss, 2015 ; Olivares et al, 2021 ), recent studies have aimed to determine if Epo modulates the hypercapnic ventilatory response to CO 2 (HcVR). Searching for an influence of Epo in HcVR is relevant because the central CO 2 /H + chemosensitivity is essential.…”

CO2-dependent opening of an inwardly rectifying K+ channel

“…Firstly, they need to possess a transducer molecule that responds to alterations of CO 2 , HCO 3 – or pH. Secondly, they have to project to areas responsible for initiating chemoreflexes and finally, once stimulated they must initiate a physiological response [7, 20, 21]. K + channels that are highly sensitive to acidification and react by closing are popular candidates for chemosensory transducers.…”