Contributions of CO₂, pH_i, and pH_o to the Signaling Pathway of Chemosensitive Neurons in the Locus Coeruleus

Central chemosensitive neurons increase their firing rate (FR) upon exposure to hypercapnic acidosis (HA: 15% CO ₂ , pH _o 7.0). Multiple signaling pathways have been proposed to account for this increase including changes in Ca ²⁺ , CO ₂ , pH _i , and pH _o . To determine the relative contributions of pH _i , pH _o , and CO ₂ to an increased FR, we used the rapid diffusion of a weak acid technique to clamp pH _i . A change in pH _i is believed to be the major signal in the chemosensitive (CS) response due to strong correlations between the degree of intracellular acidification and the increase of FR in HA (P<0.05). In fact, an intracellular acidification (0.24 ± 0.04 U) with no change in pH _o or CO ₂ elicits an increase in FR of 1.4 ± 0.5 Hz. However, this FR response can still be elicited without any change in pH _i (1.4 ± 0.1 Hz). Only when both pH _i and pH _o are clamped, does hypercapnia not result in an increase in FR (0.4 ± 0.3 Hz in 5% CO ₂ to 0.16 ± 0.1 Hz in 15% CO ₂ ). Thus, the increase in FR seen upon HA with pH _i clamped is likely due to the change in pH _o (0.45 U) during the HA exposure. Our data suggest that pH _i and pH _o can both lead to an increase in FR in response to HA, while CO ₂ alone does not appear to have a significant contribution. It appears that pH _i or pH _o saturates the FR response because FR with HA is not different than FR with pH _i only or pH _o only. These data strongly support the multiple factors model of chemosensitivity. [NIH grants RO1 HL56683 and F32 HL80877].