Ca ²⁺-Activated K⁺ Channels Limit the Chemosensitive Response of Locus Coeruleus (LC) Neurons

LC neurons are chemosensitive, increasing firing rate in response to hypercapnia through pH inhibition of K ⁺ channels. This "accelerator" pathway is believed to set central respiratory gain. Using whole cell patch clamp, we found that hypercapnia activates L-type Ca ²⁺ currents in LC neurons that increase early in life (from P1–P15) in rats. Using fluorescence imaging microscopy, we showed that these Ca ²⁺ currents lead to a rise in cellular Ca ²⁺ . This increased Ca ²⁺ could lead to activation of LC neuron K _Ca channels from P1–P15, resulting in neuronal hyperpolarization and a decreased magnitude of the firing rate response to hypercapnia with age. Consistent with this hypothesis, the K _Ca channel inhibitor paxilline enhanced the firing rate response of LC neurons to hypercapnia in an age-dependent manner. Further, the magnitude of the firing rate response of LC neurons to hypercapnia (determined as the Chemosensitivity Index) decreased with age from P1–P15 in parallel with the increase in the CO ₂ -activated Ca ²⁺ channel activity. We are studying the development of Ca ²⁺ and K _Ca channels in LC neurons using voltage clamp and immunohistochemical techniques. We propose a novel role for Ca ²⁺ in LC neurons, activating a "brake" pathway that can lead to decreased central respiratory gain. Abnormalities of this pathway could result in breathing disorders. [NIH R01 HL56683, AHA Great Rivers Affiliate Predoctoral Fellowship].