Serotonergic Raphe Neurons Express TASK Channel Transcripts and a TASK-Like pH- and Halothane-Sensitive K⁺Conductance

Abstract

The recently described two-pore-domain K+ channels, TASK-1 and TASK-3, generate currents with a unique set of properties; specifically, the channels produce instantaneous open-rectifier (i.e., "leak") K+ currents that are modulated by extracellular pH and by clinically useful anesthetics. In this study, we used histochemical and in vitro electrophysiological approaches to determine that TASK channels are expressed in serotonergic raphe neurons and to show that they confer a pH and anesthetic sensitivity to these neurons. By combining in situ hybridization for TASK-1 or TASK-3 with immunohistochemical localization of tryptophan hydroxylase, we found that a majority of serotonergic neurons in both dorsal and caudal raphe cell groups contain TASK channel transcripts (approximately 70-90%). Whole-cell voltage-clamp recordings were obtained from raphe cells that responded to 5-HT in a manner characteristic of serotonergic neurons (i.e., with activation of an inwardly rectifying K+ current). In those cells, we isolated an endogenous K+ conductance that had properties expected of TASK channel currents; raphe neurons expressed a joint pH- and halothane-sensitive open-rectifier K+ current. The pH sensitivity of this current (pK approximately 7.0) was intermediate between that of TASK-1 and TASK-3, consistent with functional expression of both channel types. Together, these data indicate that TASK-1 and TASK-3 are expressed and functional in serotonergic raphe neurons. The pH-dependent inhibition of TASK channels in raphe neurons may contribute to ventilatory and arousal reflexes associated with extracellular acidosis; on the other hand, activation of raphe neuronal TASK channels by volatile anesthetics could play a role in their immobilizing and sedative-hypnotic effects.

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.…”

Central serotonin neurons are required for arousal to CO 2

“…There is recent evidence that acid sensing ion channels in the nucleus accumbens mediate a portion of the limbic response to hypercapnia (24), but the neurons and pathways responsible for the arousal response to hypercapnia have not been identified. Given the involvement of midbrain 5-HT neurons in sleep/wake regulation and their ability to sense pH changes, it has been proposed that midbrain 5-HT neurons initiate the arousal response to hypercapnia (11,13,25,26).We tested this hypothesis using genetically modified mice in which deletion of Lmx1b in Pet1-expressing cells leads to a selective and near-complete reduction in the number of 5-HT neurons in the brain (27). As neonates, these mice hemizygous for ePet1-Cre and homozygous for floxed Lmx1b (Lmx1b f/f;e-Pet1-Cre/+ or Lmx1b f/f/p ) have severely impaired breathing and a delayed growth rate compared with mice homozygous for floxed Lmx1b but lacking a ePet1-Cre allele (Lmx1b f/f or WT) mice (28).…”

Knockout of the gene encoding the K2P channel KCNK7 does not alter volatile anesthetic sensitivity

“…The most diverse family of K channels is the tandem pore (K 2P ) family [7]. These K channels are also known as background, baseline or leak K channels because they are responsible for a resting K conductance in certain excitable cells [5,9,26]. Fifteen unique K 2P channel sequences exist in the human genome, organized into six subfamilies based on sequence and functional homology [2].…”