Gene Expression and Signaling Pathways by Extracellular Acidification

Abstract

The respiratory response to extracellular acidosis by hypercapnia is mediated by central chemoreceptor neurons in the medulla oblongata [1]. There are actually two defined groups of respiratory neurons. The dorsal group of neurons is located in and near the nucleus of the tractus solitarius and their activity is regulated by changes in the arterial partial pressure of CO2 (Pco2), O2 (Po2) or H . The ventral group is a long column of neurons that extends through the nucleus ambiguous and retroambiguous in the ventrolateral medulla. In addition to reacting to peripheral stimuli, the ventral neurons detect changes in the H and/or CO2 concentrations in the cerebrospinal fluid (CSF) and brain interstitial fluid [2]. The capacity to detect these changes is called central chemosensitivity. According to the finding that in cats the discharge frequency of ventral medullary surface (VMS) neurons is increased with lowered pH of CSF, the H concentration seems to be a stimulant of central chemosensitivity [3-6]. Carbon dioxide readily penetrates membranes, whereas H and HCO3 penetrate slowly. The CO2 that enters the brain and CSF is promptly hydrated. The H2CO3 dissociates, so that the local H concentration rises. Therefore, the effects of CO2 on respiration are mainly due to CO2 movement into the CSF, where it increases the H concentration and stimulates receptors/sensors for H. Thus, the direct stimulant of the central chemosensitive neurons may be H rather than CO2 [7, 8]. It is still not clear how H excites the H-sensitive (chemosensitive) neurons in the VMS. There is some evidence for H-sensing ionic channels in sensory neurons: H activates Na conductance in small neurons of the rat trigeminal ganglion [9]; H activates Ca channel in rat sensory neurons [10]; a stepwise reduction in extracellular pH induced an increase in Na current in small dorsal root ganglion cells of the frog [11]; and H and capsaicin share a common mechanism of neuronal activation in rat dorsal root ganglion cells [12]. The H-sensitive neurons in the VMS may also have H-sensing ionic channels/sensors or similar mechanisms for reacting to extracellular H changes. Few studies have investigated the identification of chemosensitive molecules responsible for respiratory regulation in the VMS. Not long ago, Waldmann et al. succeeded in cloning the H-gated cation channel (ASIC, for acid-sensing ionic channel) that belongs to the amiloride-sensitive Na channel/degenerin family of ion channels [13]. ASIC is expressed in dorsal root ganglia and is also distributed