An alternative approach to the identification of respiratory central chemoreceptors in the brainstem

Central chemoreceptors (CCRs) play a crucial role in autonomic respiration. Although a variety of brainstem neurons are CO(2) sensitive, it remains to know which of them are the CCRs. In this article, we discuss a potential alternative approach that may allow an access to the CCRs. This approach is based on identification of specific molecules that are CO(2) or pH sensitive, exist in brainstem neurons, and regulate cellular excitability. Their molecular identity may provide another measure in addition to the electrophysiologic criteria to indicate the CCRs. The inward rectifier K(+) channels (Kir) seem to be some of the CO(2) sensing molecules, as they regulate membrane potential and cell excitability and are pH sensitive. Among homomeric Kirs, we have found that even the most sensitive Kir1.1 and Kir2.3 have pK approximately 6.8, suggesting that they may not be capable of detecting hypocapnia. We have studied their biophysical properties, and identified a number of amino acid residues and molecular motifs critical for the CO(2) sensing. By comparing all Kirs using the motifs, we found the same amino acid sequence in Kir5.1, and demonstrated the pH sensitivity in heteromeric Kir4.1 and Kir5.1 channels to be pK approximately 7.4. In current clamp, we show evidence that the Kir4.1-Kir5.1 can detect P(CO(2)) changes in either hypercapnic or hypocapnic direction. Our in-situ hybridization studies have indicated that they are coexpressed in brainstem cardio-respiratory nuclei. Thus, it is likely that the heteromeric Kir4.1-Kir5.1 contributes to the CO(2)/pH sensitivity in these neurons. We believe that this line of research intended to identify CO(2) sensing molecules is an important addition to current studies on the CCRs.