Acid-Sensing Ion Channels Contribute to Transduction of Extracellular Acidosis in Rat Carotid Body Glomus Cells

Abstract

Abstract-Carotid body chemoreceptors sense hypoxemia, hypercapnia, and acidosis and play an important role in cardiorespiratory regulation. The molecular mechanism of pH sensing by chemoreceptors is not clear, although it has been proposed to be mediated by a drop in intracellular pH of carotid body glomus cells, which inhibits a K ϩ current. Recently, pH-sensitive ion channels have been described in glomus cells that respond directly to extracellular acidosis. In this study, we investigated the possible molecular mechanisms of carotid body pH sensing by recording the responses of glomus cells isolated from rat carotid body to rapid changes in extracellular pH using the whole-cell patch-clamping technique. Extracellular acidosis evoked transient inward current in glomus cells that was inhibited by the acid-sensing ion channel (ASIC) blocker amiloride, absent in Na ϩ -free bathing solution, and enhanced by either Ca 2ϩ -free buffer or addition of lactate. In addition, ASIC1 and ASIC3 were shown to be expressed in rat carotid body by quantitative PCR and immunohistochemistry. In the current-clamp mode, extracellular acidosis evoked both a transient and sustained depolarizations. The initial transient component of depolarization was blocked by amiloride, whereas the sustained component was eliminated by removal of K ϩ from the pipette solution and partially blocked by the TASK (tandem-p-domain, acid-sensitive K ϩ channel) blockers anandamide and quinidine. The results provide the first evidence that ASICs may contribute to chemotransduction of low pH by carotid body chemoreceptors and that extracellular acidosis directly activates carotid body chemoreceptors through both ASIC and TASK channels. (Circ Res. 2007;101:1009-1019.)Key Words: carotid body Ⅲ ASIC Ⅲ glomus cell Ⅲ chemoreceptors Ⅲ pH sensitivity T he carotid bodies function as major peripheral chemoreceptors sensing changes in arterial blood oxygen, carbon dioxide, and pH in mammals. [1][2][3] Glomus type I cells are generally accepted as the chemosensitive elements activated by hypoxemia, hypercapnia, and acidosis. 3 The common cellular mechanism for glomus cell transduction is the release of neurotransmitters such as ATP, acetylcholine, and dopamine as a result of an increase in intracellular Ca 2ϩ caused by stimulus-induced membrane depolarization. 4 -7 This leads to synaptic activation of adjacent carotid nerve endings that elicits both hyperventilation and sympathetic activation. 1,8 The molecular identity of the P O2 , P CO2 , and pH sensors is still an important question. The depolarization induced by hypoxemia has been ascribed to a closure of K ϩ channels including large-conductance, Ca 2ϩ -activated potassium (BK) channels. 3,9 -12 The transduction of acidosis to membrane depolarization was proposed to be mediated by a drop in intracellular pH which would inhibit 1 or more types of K ϩ channels, leading to membrane depolarization. 3,13,14 The findings of extracellular pH-sensitive ion conductances, including pH-sensitive Cl Ϫ currents 15 and...

Chronic hypoxia-induced acid-sensitive ion channel expression in chemoafferent neurons contributes to chemoreceptor hypersensitivity

“…To our knowledge, ASIC have not been reported in postganglionic sympathetic neurons in the SCG, and the low levels of ASIC we observed in this structure may be expressed by SIF cells in the ganglion. SIF cells are functionally and morphologically similar to carotid body type I cells, which do express ASIC (7,43,46). ASIC3 expression has been previously reported in normal NG, as well as PG (13).…”

“…It was also reported that "intercluster spaces" were devoid of staining, suggesting that ASIC are not present in nerve fibers and terminals (46). However, these latter results cannot be considered conclusive because the exquisitely slender nerve fibers and terminals that form synapses are not distinct from type I cells in immunofluorescence preparations.…”

François Abboud

“…[1][2][3][4] But, work soon progressed to the molecular and genetic level, with Abboud's particular focus being the form and function of baroreceptor neurons. [5][6][7][8][9] As Abboud explained in a recent interview, however, research is just one third of his professional passion. He is also, in equal parts, a dedicated physician and mentor..…”

Sensing Tension

“…First, carotid body glomus cells express ASIC1 and ASIC3 and, to a lesser extent, ASIC2. 42 Second, carotid body glomus cells have pH-gated currents that resemble ASIC channels and are partially amiloride sensitive. 42 Third, cardiovascular responses to chemoreceptor stimulation with carotid artery occlusion are attenuated in ASIC3 and ASIC1/ASIC3 double-null mice.…”

“…42 Second, carotid body glomus cells have pH-gated currents that resemble ASIC channels and are partially amiloride sensitive. 42 Third, cardiovascular responses to chemoreceptor stimulation with carotid artery occlusion are attenuated in ASIC3 and ASIC1/ASIC3 double-null mice. 43 Together these findings suggest that ASIC proteins may participate in pH sensing in arterial chemoreceptors.…”