CO2 chemoreception in cardiorespiratory control.

Considerable progress has been made elucidating the cellular signals and ion channel targets involved in the response to increased CO2/H+ of brain stem neurons from chemosensitive regions. Intracellular pH (pHi) does not exhibit recovery from an acid load when extracellular pH (pHo) is also acid. This lack of pHi recovery is an essential but not unique feature of all chemosensitive neurons. These neurons have pH-regulating transporters, especially Na+/H+ exchangers, but some may also contain HCO3--dependent transporters as well. Studies in locus ceruleus (LC) neurons have shown that firing rate will increase in response to decreased pHi or pHo but not in response to increased CO2 alone. A number of K+ channels, as well as other channels, have been suggested to be targets of these pH changes with a fall of pH inhibiting these channels. In neurons from some regions it appears that multiple signals and multiple channels are involved in their chemosensitive response while in neurons from other regions a single signal and/or channel may be involved. Despite the progress, a number of key issues remain to be studied. A detailed study of chemosensitive signaling needs to be done in neurons from more brain stem regions. Fully describing the chemosensitive signaling pathways in brain stem neurons will offer new targets for therapies to alter the strength of central chemosensitivity and will yield new insights into the reason why there are multiple central chemoreceptive sites.