Contributions of CO2, pHi, and pHo to the signaling pathway of chemosensitive neurons in the locus coeruleus

Abstract

Central chemosensitive neurons increase their firing rate (FR) upon exposure to hypercapnic acidosis (HA: 15% CO2, pHo 7.0). Multiple signaling pathways have been proposed to account for this increase including changes in Ca2+, CO2, pHi, and pHo. To determine the relative contributions of ΔpHi, ΔpHo, and CO2 to an increased FR, we used the rapid diffusion of a weak acid technique to clamp pHi. A change in pHi 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 pHo or CO2 elicits an increase in FR of 1.4 ± 0.5 Hz. However, this FR response can still be elicited without any change in pHi (1.4 ± 0.1 Hz). Only when both pHi and pHo are clamped, does hypercapnia not result in an increase in FR (0.4 ± 0.3 Hz in 5% CO2 to 0.16 ± 0.1 Hz in 15% CO2). Thus, the increase in FR seen upon HA with pHi clamped is likely due to the change in pHo (0.45 U) during the HA exposure. Our data suggest that ΔpHi and ΔpHo can both lead to an increase in FR in response to HA, while CO2 alone does not appear to have a significant contribution. It appears that ΔpHi or ΔpHo saturates the FR response because ΔFR with HA is not different than ΔFR with ΔpHi only or ΔpHo only. These data strongly support the multiple factors model of chemosensitivity. [NIH grants RO1 HL56683 and F32 HL80877].