A role for TASK-1 (KCNK3) channels in the chemosensory control of breathing

Abstract

Acid-sensitive K+ channels of the tandem P-domain K+-channel family (TASK-1 and TASK-3) have been implicated in peripheral and central respiratory chemosensitivity; however, because of the lack of decisive pharmacological agents, the final proof of the role of the TASK channel in the chemosensory control of breathing has been missing. In the mouse, TASK-1 and TASK-3 channels are dispensable for central respiratory chemosensitivity (Mulkey et al., 2007). Here, we have used knock-out animals to determine whether TASK-1 and TASK-3 channels play a role in the carotid body function and chemosensory control of breathing exerted by the carotid body chemoreceptors. Ventilatory responses to hypoxia (10% O2 in inspired air) and moderate normoxic hypercapnia (3-6% CO2 in inspired air) were significantly reduced in TASK-1 knock-out mice. In contrast, TASK-3-deficient mice showed responses to both stimuli that were similar to those developed by their wild-type counterparts. TASK-1 channel deficiency resulted in a marked reduction of the hypoxia (by 49%)- and CO2 (by 68%)-evoked increases in the carotid sinus nerve chemoafferent discharge recorded in the in vitro superfused carotid body/carotid sinus nerve preparations. Deficiency in both TASK-1 and TASK-3 channels increased baseline chemoafferent activity but did not cause a further reduction of the carotid body chemosensory responses. These observations provide direct evidence that TASK-1 channels contribute significantly to the increases in the carotid body chemoafferent discharge in response to a decrease in arterial P(O2) or an increase in P(CO2)/[H+]. TASK-1 channels therefore play a key role in the control of ventilation by peripheral chemoreceptors.

Figure 1.

TASK-1 channel is essential for the development of normal ventilatory responses to hypoxia and CO₂ in mice. A, Ventilatory responses to hypoxia (10% O₂ in the inspired air) in conscious TASK-1-deficient mice (TASK-1^−/−) and their wild-type counterparts (TASK^+/+). B, Ventilatory responses to varying levels of normoxic hypercapnia in TASK-1^−/− and TASK^+/+ mice. C, Phrenic nerve responses to an increase in P_CO2/[H⁺] in in situ brainstem–spinal cord preparations with denervated peripheral chemoreceptors from TASK-1^−/− and TASK^+/+ mice. Top, Raw data showing time-condensed records of integrated phrenic nerve activity (IPNA) in basal conditions (P_CO2 26 mmHg, pH 7.52) and during respiratory acidosis (P_CO2 60 mmHg, pH 7.24). Middle, Results are presented as waveform averages of the integrated phrenic nerve activity for 60 respiratory cycles at basal conditions and during respiratory acidosis. Bottom, Summary data of changes in minute respiratory output (phrenic amplitude × respiratory rate) in response to increases in P_CO2/[H⁺]. Data are presented as means ± SE. Numbers in parentheses indicate sample sizes. *p < 0.05, significantly different from TASK^+/+ response.

Figure 2.

TASK-3 channel is not required for the development of the ventilatory responses to hypoxia and CO₂ in mice. A, Ventilatory responses to hypoxia (10% O₂ in the inspired air) in conscious TASK-3-deficient mice (TASK-3^−/−) and their wild-type counterparts (TASK^+/+). B, Ventilatory responses to varying levels of normoxic hypercapnia in TASK-3^−/− and TASK^+/+ mice. Data are presented as means ± SE. Numbers in parentheses indicate sample sizes.

Figure 3.

Impaired carotid body function in TASK-deficient mice. A, Representative raw data showing hypoxia-evoked increases in the carotid sinus nerve (CSN) chemoafferent discharge recorded in the in vitro superfused carotid body/carotid sinus nerve preparations taken from the TASK-1-deficient mice (TASK-1^−/−), TASK-1- and TASK-3-deficient mice (TASK-1/3^−/−), and their wild-type counterparts (TASK^+/+). B, Raw data illustrating CO₂-evoked increases in the carotid sinus nerve chemoafferent discharge recorded in the in vitro superfused carotid body/carotid sinus nerve preparations taken from TASK-1^−/−, TASK-1/3^−/−, and TASK^+/+ mice. C, D, Summary data of the mean peak hypoxia (C)- and CO₂ (D)-induced increases in discharge frequency of the carotid sinus nerve in preparations taken from TASK-1^−/−, TASK-1/3^−/−, and TASK^+/+ mice. E, F, Summary data of the mean integral of hypoxia (E)- and CO₂ (F)-induced increases in discharge frequency (∫ΔFF) of the carotid sinus nerve in preparations taken from TASK-1^−/−, TASK-1/3^−/−, and TASK^+/+ mice. Data are presented as means ± SE. Numbers in parentheses indicate sample sizes. FF, Discharge frequency. *p < 0.05, significantly different from TASK^+/+ under the same conditions.

Figure 4.

Single-unit analysis of the carotid sinus nerve responses to chemosensory stimulation in TASK-deficient mice. A, Representative raw data of the discharge frequency profiles of eight carotid sinus nerve single chemoafferent fibers recorded under basal conditions and during hypoxic stimulation in the in vitro superfused carotid body/carotid sinus nerve preparations taken from the TASK-1-deficient mice (TASK-1^−/−; right) and their wild-type counterparts (TASK^+/+; left). B, Summary data of the mean peak hypoxia-induced increases in discharge frequency (left) and mean integral of the hypoxia-induced increase in discharge frequency (∫ΔFF; right) of the carotid sinus nerve chemoafferent fibers in preparations taken from TASK-1^−/−, TASK-1/3^−/−, and TASK^+/+ mice. C, Summary data of the mean peak CO₂-induced increases in discharge frequency and mean integral of CO₂-induced increase in discharge frequency (∫ΔFF) of the carotid sinus nerve chemoafferent fibers in preparations taken from TASK-1^−/−, TASK-1/3^−/−, and TASK^+/+ mice. Data are presented as means ± SE. Numbers in parentheses indicate sample sizes. FF, Discharge frequency. *p < 0.05, significantly different from TASK^+/+ under the same conditions.