Proton detection and breathing regulation by the retrotrapezoid nucleus

Abstract

We discuss recent evidence which suggests that the principal central respiratory chemoreceptors are located within the retrotrapezoid nucleus (RTN) and that RTN neurons are directly sensitive to [H(+) ]. RTN neurons are glutamatergic. In vitro, their activation by [H(+) ] requires expression of a proton-activated G protein-coupled receptor (GPR4) and a proton-modulated potassium channel (TASK-2) whose transcripts are undetectable in astrocytes and the rest of the lower brainstem respiratory network. The pH response of RTN neurons is modulated by surrounding astrocytes but genetic deletion of RTN neurons or deletion of both GPR4 and TASK-2 virtually eliminates the central respiratory chemoreflex. Thus, although this reflex is regulated by innumerable brain pathways, it seems to operate predominantly by modulating the discharge rate of RTN neurons, and the activation of RTN neurons by hypercapnia may ultimately derive from their intrinsic pH sensitivity. RTN neurons increase lung ventilation by stimulating multiple aspects of breathing simultaneously. They stimulate breathing about equally during quiet wake and non-rapid eye movement (REM) sleep, and to a lesser degree during REM sleep. The activity of RTN neurons is regulated by inhibitory feedback and by excitatory inputs, notably from the carotid bodies. The latter input operates during normo- or hypercapnia but fails to activate RTN neurons under hypocapnic conditions. RTN inhibition probably limits the degree of hyperventilation produced by hypocapnic hypoxia. RTN neurons are also activated by inputs from serotonergic neurons and hypothalamic neurons. The absence of RTN neurons probably underlies the sleep apnoea and lack of chemoreflex that characterize congenital central hypoventilation syndrome.

Brainstem mechanisms underlying the cough reflex and its regulation

“…They may arise from more rostral expiration-related regions such as the BötC (Bongianni et al, 1998;Shannon et al, 2000; for review see also Iscoe 1998;Pantaleo et al, 2002;Shannon et al, 2004) or the RTN/ pFRG (Onimaru and Homma 2003;Mulkey et al, 2004;Janczewski and Feldman 2006;Guyenet and Mulkey 2010;Guyenet et al, 2016;Ikeda et al, 2017) as well as from the limbic system and the periaqueductal gray (Subramanian and Holstege 2009;Jones et al, 2016). Some recent findings are in contrast with the current concept that structures caudal to the obex are unnecessary for eupneic breathing.…”

“…Fellin 2009). It has been proposed that astrocytes in the respiratory network may contribute to the characteristic of inspiratory activity (Hulsmann et al, 2000;Schnell et al, 2011;Okada et al, 2012;Oku et al, 2016) and play a crucial role in central chemoreception within the RTN (Gourine et al, 2010;Guyenet et al, 2016). The finding that ozone-induced pulmonary inflammation results in a specific activation of vagal afferents that induces astroglial cellular alterations in the NTS (Chounlamountry et al, 2015 also for further Refs.)…”

“…This structure functions as a chemosensitive center that detects environmental CO 2 and expresses a paired-like homeobox 2b gene (Phox2b). Neurons located in this area in neonatal rats are intrinsically CO 2 -sensitive (Mulkey et al, 2004;Guyenet and Mulkey 2010;Guyenet et al, 2016;Ikeda et al, 2017). Interestingly, Phox2b mutations have been described in most human cases of central congenital hypoventilation syndrome (Amiel et al, 2003).…”

Phosphatidylinositol (4,5)-bisphosphate dynamically regulates the K2P background K+ channel TASK-2

“…The K 2P K + channel known as TASK-2 (also K 2P 5.1)2425 is involved in bicarbonate reabsorption in the proximal tubules of the kidney26, the central detection of CO 2 and O 2 by chemo-sensitive neurons implicated in breathing control272829, and in the hearing function through an essential role in outer sulcus cells possibly in K + recycling30. From a pathophysiological point of view, TASK-2 has been implicated in a predisposition to Balkan endemic nephropathy31 through a dominant negative missense mutation supressing function3233, in the pathogenesis of multiple sclerosis and rheumatoid arthritis in humans34, and in murine inflammatory bowel disease35.…”

CO2-Induced ATP-Dependent Release of Acetylcholine on the Ventral Surface of the Medulla Oblongata

“…Current concepts of central respiratory CO 2 chemosensitivity pose that RTN neurons are intrinsically pH-sensitive (this chemosensitivity is believed to be mediated by proton sensitive GPCRs and K + channels) [35], and play the key role in relaying changes in brainstem parenchymal pH into a modified pattern of breathing [36]. This model, however, cannot explain why RTN neurones are not able to mount an appropriate respiratory response when the pH-sensitivity of neighbouring astrocytes is compromised [37–39].…”