Abstract
Key points: We studied the role of the large-conductance Ca2+ -activated K+ channel (BK) and voltage-dependent K+ channels (Kv) on [Ca2+ ]i responses to a wide range of hypoxia at different resting cell membrane potential (Em ). BK/Kv were mostly closed at rest in normoxia. BK/Kv became basally active when cells were depolarized by elevated [KCl]o (>12 mm). Regardless of whether BK/Kv were closed or basally open, hypoxia-induced elevation of [Ca2+ ]i was enhanced 2- to 3-fold by inhibitors of BK/Kv. Hypoxia-induced elevation of [Ca2+ ]i was enhanced ∼2-fold by an inhibitor of Kv2, a major Kv in rat glomus cells. Hypoxia did not inhibit BK in inside-out patches. Our study supports a scheme in which activation of BK/Kv strongly limits the magnitude of hypoxia-induced [Ca2+ ]i rise, with Kv having a much greater effect than BK. Large-conductance KCa (BK) and other voltage-dependent K+ channels (Kv) are highly expressed in carotid body (CB) glomus cells, but their role in hypoxia-induced excitation is still not well defined and remains controversial. We addressed this issue by studying the effects of inhibitors of BK (IBTX) and BK/Kv (TEA/4-AP) on [Ca2+ ]i responses to a wide range of hypoxia at different levels of resting cell membrane potential (Em ). IBTX and TEA/4-AP did not affect the basal [Ca2+ ]i in isolated glomus cells bathed in 5 mm KClo , but elicited transient increases in [Ca2+ ]i in cells that were moderately depolarized (11-20 mV) by elevation of [KCl]o (12-20 mm). Thus, BK and Kv were mostly closed at rest and activated by depolarization. Four different levels of hypoxia (mild, moderate, severe, anoxia) were used to produce a wide range of [Ca2+ ]i elevation (0-700 nm). IBTX did not affect the rise in [Ca2+ ]i , but TEA/4-AP strongly (∼3-fold) enhanced [Ca2+ ]i rise by moderate and severe levels of hypoxia. Guangxitoxin, a Kv2 blocker, inhibited the whole-cell current by ∼50%, and enhanced 2-fold the [Ca2+ ]i rise elicited by moderate and severe levels of hypoxia. Anoxia did not directly affect BK, but activated BK via depolarization. Our findings do not support the view that hypoxia inhibits BK/Kv to initiate or maintain the hypoxic response. Rather, our results show that BK/Kv are activated as glomus cells depolarize in response to hypoxia, which then limits the rise in [Ca2+ ]i . Inhibition of Kv may provide a mechanism to enhance the chemosensory activity of the CB and ventilation.