| Specialized neurons located in different regions of the brainstem have been identified as central respiratory chemoreceptors (CRC), whose primary role is to transduce changes in CO2/H+ levels into an electrical response that leads to adjustments in ventilation and restoration of normal levels of arterial CO2. Despite intensive research, the cellular mechanisms mediating this response have remained elusive. Nevertheless, it is known that during hypercapnic acidosis (HA), intracellular pH (pH i) in CRC falls and no pHi recovery occurs; while in non-chemosensitive neurons, pHi recovery is seen during HA. CRC also change their firing rate in response to acidification, suggesting a link between pH i regulation and the electrical response. To investigate potential mechanisms for these responses, we developed a mathematical model to study pHi regulation in CRC and non-chemosensitive neurons. The model includes kinetic descriptions of the Na+/H+ exchanger, the Cl -/HCO3- exchanger, and carbonic anhydrase as well as cell volume regulation (via NKCC and KCC cotransporters) and passive diffusion of major ions. Simulation experiments demonstrated that differences between CRC and non-chemosensitive neurons cannot be explained by different NHE isoforms; however, alterations in this transport mechanism affect the ability of the neuron to regulate pHi, indicating that different levels of expression and/or an unidentified isoform may participate. To address the link between pHi regulation and cell excitability, the model was expanded to include mechanisms for action-potential generation. To accomplish this, parameters for fast and slow Na+ and K + currents were identified using a typical Hodgkin-Huxley (HH) excitable cell model, and then incorporated into our transport model. Simulation experiments revealed that (1) the small changes in ionic composition seen during HA are sufficient to alter the electrical state of the neuron and drive the HA-induced increase in firing frequency, demonstrating that Ca2+ and pH sensitive K+ channels are not required for the excitable response, and (2) HCO3- is an important element for modulation of the excitable response during HA. We conclude that differences in multiple, not single, cellular mechanisms mediate the different behaviors of CRC and non-chemosensitive neurons. |
