CaV3.2 T-type Ca²⁺channels mediate the augmented calcium influx in carotid body glomus cells by chronic intermittent hypoxia

Abstract

] i ) in glomus cells, the primary oxygensensing cells, is an essential step for carotid body activation by hypoxia. In the present study, we examined the effects of CIH on the glomus cell [Ca 2ϩ ] i response to hypoxia and assessed the underlying mechanisms. Glomus cells were harvested from adult rats or wild-type mice treated with 10 days of either room air (control) or CIH (alternating cycles of 15 s of hypoxia and 5 min of room air; 9 episodes/h; 8 h/day). CIH-treated glomus cells exhibited an enhanced [Ca 2ϩ ] i response to hypoxia, and this effect was absent in the presence of 2-(4-cyclopropylphenyl)-N-((1R)-1-[5-[(2,2,2-trifluoroethyl)oxo]-pyridin-2-yl]ethyl)acetamide (TTA-A2), a specific inhibitor of T-type Ca 2ϩ channels, and in voltage-gated calcium channel, type 3.2 (CaV3.2), null glomus cells. CaV3.2 knockout mice exhibited an absence of CIH-induced hypersensitivity of the carotid body. CIH increased reactive oxygen species (ROS) levels in glomus cells. A ROS scavenger prevented the exaggerated TTA-A2-sensitive [Ca 2ϩ ] i response to hypoxia. CIH had no effect on CaV3.2 mRNA levels. CIH augmented Ca 2ϩ currents and increased CaV3.2 protein in plasma membrane fractions of human embryonic kidney-293 cells stably expressing CaV3.2, and either a ROS scavenger or brefeldin-A, an inhibitor of protein trafficking, prevented these effects. These findings suggest that CIH leads to an augmented Ca 2ϩ influx via ROSdependent facilitation of CaV3.2 protein trafficking to the plasma membrane. sleep apnea; voltage-gated Ca 2ϩ channels; hypertension; protein trafficking; oxidative stress SLEEP-DISORDERED BREATHING with recurrent apnea is a major clinical problem affecting an estimated 9% of adult women and 24% of adult men in the United States (Young et al.

Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor‐dependent sensory long‐term facilitation in naïve carotid bodies

“…However, PEG‐catalase had no effect on induction of sensory LTF in the present study and, as such, our data do not support a role for H 2 O 2 , proposed as the mechanistic lynch pin between O 2·¯ and glomus cell Cav3.2 modification in CIH‐preconditioned sensory LTF (Makarenko et al . ).…”

“…) and a T‐type voltage‐gated calcium channel, type 3.2 (CaV3.2) (Makarenko et al . ). However, sensory LTF induced by acute stimuli in the absence of CIH preconditioning may be mediated by a different mechanism.…”

“…The mechanism(s) responsible for the induction and maintenance phases of CB sensory LTF are not fully resolved. When sensory LTF is induced by a combination of CIH preconditioning and AIH, maintenance is probably contingent on a presynaptic (glomus cell) reactive oxygen species (ROS)-dependent mechanism involving 5-HT, NADPH oxidase/ROS signalling (Peng et al 2009) and a T-type voltage-gated calcium channel, type 3.2 (CaV3.2) (Makarenko et al 2016). However, sensory LTF induced by acute stimuli in the absence of CIH preconditioning may be mediated by a different mechanism.…”

Gene expression analyses reveal metabolic specifications in acute O2‐sensing chemoreceptor cells

“…), and it has recently been suggested that the Cav3.2 channel subtype mediates the CB over‐activation induced by chronic intermittent hypoxia (Makarenko et al . ). On the other hand, Cav3.2 mRNA is up‐regulated by chronic hypoxia in an Hif2α‐dependent manner in PC12 and chromaffin cells (del Toro et al .…”

Epigenetic regulation of redox state mediates persistent cardiorespiratory abnormalities after long‐term intermittent hypoxia

“…IH increases ROS levels in glomus cells, the primary O 2 sensing cells of the CB (Makarenko et al . ), nucleus tractus solitarious and rostral ventrolateral medulla, the two major brainstem areas associated with processing of sensory information from the CB, and, in AM, a major end organ of the sympathetic nervous system (Kumar et al . ; Souvannakitti et al .…”