Breaking down CO₂: bicarbonate the other side of central chemosensitivity in retrotrapezoid nucleus neurons

Carbon dioxide is a metabolic byproduct that is critically important in acid–base regulation throughout the body. When hydrated, CO₂ converts reversibly to carbonic acid and rapidly dissociates into H⁺ and HCO₃ ⁻. Throughout the body, H⁺ and HCO₃ ⁻ are regulated by different mechanisms. This regulation may be differentially influenced by changes in CO₂ homeostasis across the intracellular and extracellular domains. Thus, mechanisms of sensing CO₂, H⁺ and HCO₃ ⁻ may be conserved across physiological processes. However, in the context of breathing, the role HCO₃ ⁻ in central chemoreception is poorly understood. For over 30 years, H⁺ sensitivity in the brainstem has been largely considered the primary stimulus mediating the central respiratory chemoreflex. A growing amount of evidence suggests that a handful of cells just ventral of the facial nucleus in the retrotrapezoid nucleus (RTN) serve as important mediators of the central respiratory chemoreflex (for review see Guyenet & Bayliss, 2015). While both neurons and astrocytes cooperatively respond to H⁺/CO₂ in the RTN, chemosensitive neurons are intrinsically sensitive to H⁺ and thus pH. In this issue of The Journal of Physiology, Gonçalves and Mulkey (2018) show that HCO₃ ⁻ acts as a novel stimulus for RTN CO₂/H⁺‐sensitive neurons in vitro.

Much is known about the physiology of RTN chemosensitive neurons. The firing rate of chemosensitive RTN neurons increases in response to acidification. This increase involves multiple molecular pH‐sensitive mechanisms. Acidification inhibits potassium leak channel conductance mediated by the two‐pore acid‐sensitive potassium channel (TASK‐2) and activates second messenger signalling via the G protein‐coupled receptor 4 (GPR4), which also appears to target a possible potassium leak conductance (Guyenet & Bayliss, 2015). However, the chemosensitivity of firing rate by RTN neurons is not strictly due to pH per se as hypercapnic acidification augments the firing rate response when compared to acidification alone (Wang et al. 2013). Augmented firing rate by CO₂ during acidification can involve non‐cell autonomous mechanisms as well. For example, serotonergic neuromodulation stimulates RTN neurons by inhibiting KCNQ channels (Hawryluk et al. 2012) and activating HCN channels (Hawkins et al. 2015). Astrocytes also modulate activity of RTN chemoreceptors by releasing ATP during hypercapnia. ATP release causes P2X receptor‐dependent enhancement of inhibitory synaptic input to RTN neurons (Mulkey et al. 2006; Guyenet & Bayliss, 2015), whereas purinergic signalling that involves P2Y receptor‐dependent mechanisms activates RTN neurons either directly (Mulkey et al. 2006) or indirectly by causing regional vasoconstriction (Hawkins et al. 2017).

Gonçalves and Mulkey (2018) hypothesize the presence of a bicarbonate detection mechanism that exists in RTN neurons which is independent of the mechanisms discussed above. They confirm that this HCO₃ ⁻ sensitivity appears to manifest only in CO₂‐sensitive RTN neurons. Thus, the in situ HCO₃ ⁻ sensitivity of RTN chemosensitive neurons raises the possibility that HCO₃ ⁻ may act through one or more cellular mechanisms by which CO₂ acts as a stimulus for the RTN. Using pharmacological manipulations, the authors systematically demonstrate that the stimulation of RTN neurons by HCO₃ ⁻ neither involves KCNQ channels nor is dependent on P2X purinergic receptor signalling. Gonçalves and Mulkey further show that HCO₃ ⁻ stimulates firing rate independent of changes in pH_i and carbonic anhydrase activity by monitoring pH_i using pH indicator and using pharmacological blockade of carbonic anhydrase. Together these observations build a case for HCO₃ ⁻ signalling uniquely acting on CO₂/H⁺‐sensitive RTN neurons independent of the well‐described mechanisms by which CO₂/H⁺ stimulate firing rate.

Upon demonstrating the ability for HCO₃ ⁻ to selectively stimulate RTN CO₂/H⁺‐sensitive neurons, it is tempting to propose that HCO₃ ⁻ may be a novel stimulus for the central respiratory chemoreflex. However, two major steps are needed to validate this hypothesis. First, the cell mechanism(s) by which HCO₃ ⁻ stimulates RTN neurons must be identified. One attractive potential mechanism could involve one or more members of the bicarbonate transporter superfamily, which includes both sodium‐coupled bicarbonate transporters and the AE family of anion exchangers (e.g. Cl⁻/HCO₃ ⁻ exchangers). Second, the mechanism must also contribute to the central respiratory chemoreflex. Thus, without identifying the molecular target for HCO₃ ⁻ sensitivity in the RTN, the relevance of HCO₃ ⁻ sensitivity to respiratory drive remains an important and open question that must be addressed. These future experiments may be instrumental for defining novel targets for intervention in diseases, such as Rett syndrome and chronic obstructive pulmonary disease, where the central respiratory chemoreflex is impaired.

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Competing interests

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