Figure 6). Contribution of the purinergic signaling in the RTN region to chemosensory control of breathing.

Signals from central or peripheral chemoreceptors may affect the activity of several medullary areas, including the RTN, NTS and the ventral respiratory neurons (VRC), which affect motorneurons to respiratory muscles. The excitatory drive of ventrolateral medulla neurons operates via a direct glutamatergic and/or purinergic input from caudal NTS neurons and via a di-synaptic input that relays via the intrinsically chemosensitive neurons of RTN (Moreira et al., 2006, Takakura et al., 2006, Wenker et al., 2013). On the other hand, an essential step for hypercania-induced breathing is activation of RTN neurons which in turn send excitatory signals to activate the VRC neurons, possibly by purinergic signaling (Wenker et al., 2012, Wenker et al., 2013, Alvares et al., 2014). Chemosensitive RTN neurons are directly activated by CO₂/H⁺ by mechanisms involving inhibition of TASK2 (Wang et al., 2013) and activation of a proton-activated receptor GPR2 (Kumar et al., 2015). In addition, RTN chemoreceptors receive CO₂/H⁺-dependent excitatory purinergic drive from local astrocytes which sense CO₂/H⁺ by inhibition of Kir4.1-containing channels (Wenker et al., 2010) and release ATP by mechanisms involving Ca²⁺-dependent exocytosis or Ca²⁺-independent release through connexin channels (Cx26 primarily) (Huckstepp et al., 2010). Abbreviations: ATP, adenosine triphosfate; CB, carotid body; Glut, glutamate; iGlut, ionotropic glutamatergic receptors; MN, motor neuron; NTS, nucleus of the solitary tract; P2X, ionotropic purinergic receptors; RTN, retrotrapezoid nucleus; VMS, ventral medullary surface; VRC, ventral respiratory column.