Cellular mechanisms involved in CO₂ and acid signaling in chemosensitive neurons

Abstract

An increase in CO(2)/H(+) is a major stimulus for increased ventilation and is sensed by specialized brain stem neurons called central chemosensitive neurons. These neurons appear to be spread among numerous brain stem regions, and neurons from different regions have different levels of chemosensitivity. Early studies implicated changes of pH as playing a role in chemosensitive signaling, most likely by inhibiting a K(+) channel, depolarizing chemosensitive neurons, and thereby increasing their firing rate. Considerable progress has been made over the past decade in understanding the cellular mechanisms of chemosensitive signaling using reduced preparations. Recent evidence has pointed to an important role of changes of intracellular pH in the response of central chemosensitive neurons to increased CO(2)/H(+) levels. The signaling mechanisms for chemosensitivity may also involve changes of extracellular pH, intracellular Ca(2+), gap junctions, oxidative stress, glial cells, bicarbonate, CO(2), and neurotransmitters. The normal target for these signals is generally believed to be a K(+) channel, although it is likely that many K(+) channels as well as Ca(2+) channels are involved as targets of chemosensitive signals. The results of studies of cellular signaling in central chemosensitive neurons are compared with results in other CO(2)- and/or H(+)-sensitive cells, including peripheral chemoreceptors (carotid body glomus cells), invertebrate central chemoreceptors, avian intrapulmonary chemoreceptors, acid-sensitive taste receptor cells on the tongue, and pain-sensitive nociceptors. A multiple factors model is proposed for central chemosensitive neurons in which multiple signals that affect multiple ion channel targets result in the final neuronal response to changes in CO(2)/H(+).

Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study

“…Chemosensitive cells in both brainstem and suprapontine regions, including the ventral medulla, locus ceruleus, raphe nuclei, periaqueductal gray, hypothalamus and amygdala, strongly influence the regulation of arousal, as well as respiration and cardiovascular function. [5][6][7][8]62,63 Many acid-sensitive chemoreceptors respond selectively to decreases in extracellular fluid (ECF) pH. 6,8 Neuronal activity is often followed by intracellular alkalinization within astrocytes and acidification of brain ECF.…”

“…[5][6][7][8]62,63 Many acid-sensitive chemoreceptors respond selectively to decreases in extracellular fluid (ECF) pH. 6,8 Neuronal activity is often followed by intracellular alkalinization within astrocytes and acidification of brain ECF. 64 The degree of activity-evoked ECF acidification has been correlated with lactate accumulation.…”

“…These chemoreceptive mechanisms are highly sensitive to variations in pH and pCO 2 and also respond to variations in other metabolic parameters. [5][6][7][8] Converging evidence supports the hypothesis that patients with PD have an underlying metabolic abnormality. PD patients are unusually susceptible to experiencing panic attacks in response to various metabolic challenges, including sodium lactate infusions, 9,10 respiratory stimulation (via carbon dioxide inhalation 11 or doxapram injection 12 ) and caffeine ingestion.…”

Ventilatory roll off during sustained hypercapnia is gender specific in pekin ducks

“…The exact location of these receptors remain unknown in birds, but because of similarities in the chemical control of respiration between birds and mammals, central chemoreceptors in birds are thought to be in a similar location to those in mammals (Bouverot, 1978). Chemoreceptive neurons are spread among numerous brain stem regions (Nattie, 1999;Lahiri and Forster, 2003;Putnam et al, 2004). The arterial pH recovery observed in our study probably influenced signalling by chemosensitive neurons by altering cerebrospinal fluid (CSF) pH and intracellular pH of the neurons, but the relationship may not be direct as CSF and arterial pH are regulated differently (e.g., Nattie and Edwards, 1981).…”

Differences in tyrosine hydroxylase expression after short-term hypoxia, hypercapnia or hypercapnic hypoxia in rat carotid body

“…The expression of TH mRNA may reflect differences in the respiratory reflex among the three gas conditions. Ventilatory responses to hypoxia and/or hypercapnia were different among newborn and adult animal species (Mortola and Lanthier, 1995;Putnam et al, 2004). Thus, it must be noted that expressions of TH mRNA induced by hypoxia 340 and/or hypercapnia may vary among animal species and change during development.…”