Brainstem regulation of CO2 chemoreception is essential in matching ventilation to the metabolic demands of the organism. The principal sites involved in sensing CO2 are widespread and located throughout the medulla. There is general agreement that the changes in pH associated with an increase in PCO2 represent the appropriate stimulus to the central chemoreceptors. Although all of the sensory transduction process of CO2 are not known, modulation of neuronal activity through purinergic mechanisms and proton block of outward cationic TASK channels have good experimental support. Within the medulla, sodium-bicarbonate cotransport (NBC) is expressed principally in astrocytes. NBC is electrogenic, and when medullary glia are depolarized by either by the direct actions of CO2 or secondarily by elevated extracellular potassium associated with neuronal activity, pHe falls dramatically. Thus, glia tend to amplify the neuronal response to any given level of hypercapnia and may modulate chemoreceptor output by regulating pHe. Modulation of the glia-neuronal lactate shuttle may also affect pHe. Inhibition of monocarboxylate transporter 2 (MCT) in neurons leads to an intracellular alkalosis of neurons, an extracellular acid shift and increase in ventilation. In addition, inhibition MCT2 increases glucose uptake suggesting both lactate and glucose are used concurrently by neurons.
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