An ASIC channel for acid chemotransduction

Abstract

Spontaneous breathing requires feedback controls in which detection of blood gas and pH are critical. While O2 detection is performed by pheripheral chemoreceptors, CO2/pH-sensitive chemoreceptors are in the carotid bodies (CBs), but major sites are also within the brain (the central chemoreceptors [CCR]). CO2/pH signals are related to the acid-base status of the blood and reflect the adequacy of breathing to metabolism. Small changes in CO2/pH can affect breathing, so that a rise in Pco2 as small as 1 mm Hg produces an evident change in ventilation.1 Such a high CO2 sensitivity relies in the inherent properties of CO2/pH-sensing molecules present both in CB and CCR cells, as shown in several recent studies on CO2/pH sensing ion channels and receptors.2,3 Functional properties of most proteins can be regulated by changes in pH, as this would only require 1 or a few titratable residues of the molecule, whose protonation can lead to conformation changes that translate into changes in activity. However, to define whether those molecules have a relevant role in CO2/pH chemoreception, some more criteria should be met, including their range of pH sensitivity, their location in chemoreceptor cells, and their functional contribution to the integrated chemoreceptor response. In this regard, the molecular characterization of pH-sensitive channels and transporters has progressed considerably within the last years, but conclusive evidences of their contribution to acid chemotransduction are not so well established for many of them. The main reason for this delay is the fact that the identity of the primary sensory cells constituting CCRs and of their neuronal networks remains elusive. In vitro, neurons from many brain locations are excited or inhibited by CO2/pH changes, but it has been difficult to link this neuronal chemosensitivity to chemoreception in vivo. Moreover, in addition to chemosensitive neurons, CCRs sites may also contain neurons with other integrative functions that are not clearly distinct from chemosensitive ones in their morphological or functional properties, making their experimental study difficult.