["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend When the carotid body (CB) detects low oxygen levels (hypoxia), this leads to: (1) depolarization of the chemosensory cells (glomus cells) within the CB – the resulting increase in intracellular Ca2+ stimulates the exocytotic co‐release of vesicles containing ATP and glutamate; (2) synaptic ATP acts on postsynaptic petrosal neuron P2X2/3 receptors, and activation initiates the depolarization of petrosal afferent fibres; (3) glutamate acts on ionotropic NMDA receptors on adjacent glomus cells (paracrine) and back on the cell from which it was released (autoreceptor); and (4) increases in intracellular Ca2+ due to NMDA activation trigger the mobilization of GABA vesicles. GABA binds to GABAA receptors on adjacent glomus cells, inhibiting their excitation and dampening the CB chemoreflex response. This intrinsic ‘accelerator–brake’ mechanism sets the chemoreflex gain and modulates breathing.\n\n\n\n\n\n\n\n\n\nAbstract\nCardiorespiratory homeostasis is maintained by carotid body (CB) peripheral chemoreceptors that monitor blood oxygen and stimulate breathing. While proportionality between peripheral chemoreflex sensitivity and respiratory response is relative to hypoxia severity, the fundamental regulatory mechanisms remain unknown. We hypothesized that intercellular amino acid transmission between glomus cells modulates CB sensitivity. We identified a full complement of glutamate and gamma‐aminobutyric acid (GABA) synaptic signalling machinery in the CB. During hypoxia stimulation, glutamate acting via NMDA receptors (NMDA‐R) stimulated CB afferents while releasing GABA, which acted on GABAA receptors to rapidly attenuate afferent drive mediated by purinergic P2X receptors. We propose that this intrinsic ‘accelerator–brake’ mechanism regulates CB sensitivity to hypoxia. Further, glutamate and NMDA‐R were essential for long‐term facilitation (LTF) of respiratory chemoreflex responses induced by repeated hypoxia or glutamate exposures. The accelerator–brake mechanism establishes the set‐point of chemoreflex gain and provides plasticity for modulation, explaining ventilatory LTF to repeated bouts of hypoxia.\n\n\n\n\n\n\n\n\n\nKey points\n\nAn intra‐carotid body interaction between glutamate and GABA transmission is crucial for the generation of the biphasic carotid body afferent nerve response when stimulated with low doses of sodium cyanide.\nGlutamate stimulates the carotid body chemoreflex to increase inspiratory drive without affecting sympathetic activity, heart rate or perfusion pressure, indicating selective activation of a carotid body respiratory reflex arc.\nRepetitive application of glutamate to the carotid body sensitizes chemoreflex phrenic nerve responses producing long‐term facilitation.\n\n\n"]