Proton detection and breathing regulation by the retrotrapezoid nucleus. (19th February 2016)

• Record Type: Journal Article
• Authors: Guyenet, Patrice G.; Bayliss, Douglas A.; Stornetta, Ruth L.; Ludwig, Marie‐Gabrielle; Kumar, Natasha N.; Shi, Yingtang; Burke, Peter G. R.; Kanbar, Roy; Basting, Tyler M.; Holloway, Benjamin B.; Wenker, Ian C.
• Is Part Of: Journal of physiology. Volume 594:Number 6(2016:Mar.)
• Page Start: 1529
• Page End: 1551
• Publication Date: 2016-02-19
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP271480
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract : Left: location and core function of the retrotrapezoid nucleus (RTN). RTN neurons reside at the ventral surface of the rostral medulla oblongata. Their axonal projections, depicted on a parasagittal section of the rodent lower brainstem, target principally the respiratory pattern generator, i.e. the network of lower brainstem neurons that orchestrate the contractions of inspiratory and expiratory muscles and regulate airway patency. RTN neurons are strongly stimulated by hypercapnia and their main known function is to adjust lung ventilation so as to maintain the stability of arterial P C O 2 . This role is especially important during non‐REM sleep and quiet waking. Right: P C O 2 detection by RTN. RTN neurons detect P C O 2 primarily via changes in proton concentration. A recently uncovered mechanism relies on the expression by RTN neurons of a proton‐operated G protein‐coupled receptor (GPR4) and a proton‐sensitive resting potassium conductance (TASK‐2). Acidification also activates ventral medullary surface astrocytes. In response to this stimulus, their intracellular calcium concentration rises, causing the release of ATP which may directly activate RTN neurons via P2 receptors. Astrocytes may also activate RTN neurons by reducing local blood flow and causing tissue P C O 2 to increase. Additional putative mechanisms by which astrocytes could facilitate pH detection by RTN neurons are discussed in the review but not represented in the figure. 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.