Contributions of CO 2 , 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 ΔpH i , ΔpH 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 ΔpH i and ΔpH 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 ΔpH i or ΔpH o saturates the FR response because ΔFR with HA is not different than ΔFR with ΔpH i only or ΔpH o only. These data strongly support the multiple factors model of chemosensitivity. [NIH grants RO1 HL56683 and F32 HL80877].