Carotid body chemosensory responses in mice deficient of TASK channels

Abstract

Background K+ channels of the TASK family are believed to participate in sensory transduction by chemoreceptor (glomus) cells of the carotid body (CB). However, studies on the systemic CB-mediated ventilatory response to hypoxia and hypercapnia in TASK1- and/or TASK3-deficient mice have yielded conflicting results. We have characterized the glomus cell phenotype of TASK-null mice and studied the responses of individual cells to hypoxia and other chemical stimuli. CB morphology and glomus cell size were normal in wild-type as well as in TASK1−/− or double TASK1/3−/− mice. Patch-clamped TASK1/3-null glomus cells had significantly higher membrane resistance and less hyperpolarized resting potential than their wild-type counterpart. These electrical parameters were practically normal in TASK1−/− cells. Sensitivity of background currents to changes of extracellular pH was drastically diminished in TASK1/3-null cells. In contrast with these observations, responsiveness to hypoxia or hypercapnia of either TASK1−/− or double TASK1/3−/− cells, as estimated by the amperometric measurement of catecholamine release, was apparently normal. TASK1/3 knockout cells showed an enhanced secretory rate in basal (normoxic) conditions compatible with their increased excitability. Responsiveness to hypoxia of TASK1/3-null cells was maintained after pharmacological blockade of maxi-K+ channels. These data in the TASK-null mouse model indicate that TASK3 channels contribute to the background K+ current in glomus cells and to their sensitivity to external pH. They also suggest that, although TASK1 channels might be dispensable for O2/CO2 sensing in mouse CB cells, TASK3 channels (or TASK1/3 heteromers) could mediate hypoxic depolarization of normal glomus cells. The ability of TASK1/3−/− glomus cells to maintain a powerful response to hypoxia even after blockade of maxi-K+ channels, suggests the existence of multiple sensor and/or effector mechanisms, which could confer upon the cells a high adaptability to maintain their chemosensory function.

A revisit to O2 sensing and transduction in the carotid body chemoreceptors in the context of reactive oxygen species biology

“…In the study by Wyatt et al (2007) it was also shown that the AMPK antagonist compound C reversed the just described effects of hypoxia and AICAR on chemoreceptor cells. Although ironically, from a cynic point of view, it might be said that most of the effects seen on AMPK activation and inhibition are epiphenomenal to O 2 -sensing, because maxiK inhibition (Gomez-Niño et al, 2009a,b) and genetic elimination of TASK-1 and TASK-3 do not affect hypoxic behaviour of chemoreceptor cells (Ortega-Sáenz et al, 2010). It must be unambiguously stated that the data generated by Wyatt et al (2007) would indicate that AMPK dependent phosphorylation of K + channels in CB chemoreceptor cells mimic hypoxia and appears capable of eliciting integrated CB afferent activity, arguing in the favour that AMPK activation is a key element in the hypoxic transduction cascade.…”

Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

“…The TASK-3 channel is also overexpressed in a variety of cancers and confers hypoxia resistance on tumors (Mu et al, 2003). Knockout mice lacking one or both TASK channels display a variety of phenotypes, including impaired carotid body chemosensing (Ortega-Saenz et al, 2010), sleep fragmentation (Pang et al, 2009), antidepressive behavior (Gotter et al, 2011), primary hyperaldosteronism and low-renin essential hypertension (Davies et al, 2008;Guagliardo et al, 2012), and cardiac conduction and repolarization abnormalities Donner et al, 2011;Petric et al, 2012). An inactivating mutation in the human TASK-3 channel pore (G236R) is associated with the BirkBarel syndrome of mental retardation, hypotonia, and facial dysmorphism (Barel et al, 2008).…”

Neurotrophic Properties, Chemosensory Responses and Neurogenic Niche of the Human Carotid Body

“…Although this model of sensory transduction has been demonstrated in several animal models, it has not been studied in human tissues. We have prepared slices of human CB, to measure the secretory responses to hypoxia by amperometry, as well as dispersed CB cells to monitor the changes of cytosolic [Ca 2+ ] by microfl uorimetry (Garcia-Fernandez et al 2007 ;Ortega-Saenz et al 2010 ;Pardal et al 2000 ;Urena et al 1994 ). Representative recordings of catecholamine release from individual glomus cells subjected to low O 2 tension (PO 2 , ≈15 mmHg) and high (40 mM) potassium are illustrated in Fig.…”