An important functional role of persistent Na⁺current in carotid body hypoxia transduction

Abstract

Systemic hypoxia in mammals is sensed and transduced by the carotid body into increased action potential (AP) frequency on the sinus nerve, resulting in increased ventilation. The mechanism of hypoxia transduction is not resolved, but previous work suggested that fast Na(+) channels play an important role in determining the rate and timing of APs (Donnelly, DF, Panisello JM, and Boggs D. J Physiol. 511: 301-311, 1998). We speculated that Na(+) channel activity between APs, termed persistent Na(+) current (I(NaP)), is responsible for AP generation that and riluzole and phenytoin, which inhibit this current, would impair organ function. Using whole cell patch clamp recording of intact petrosal neurons with projections to the carotid body, we demonstrated that I(NaP) is present in chemoreceptor afferent neurons and is inhibited by riluzole. Furthermore, discharge frequencies of single-unit, chemoreceptor activity, in vitro, during normoxia (Po(2) 150 Torr) and during acute hypoxia (Po(2) 90 Torr) were significantly reduced by riluzole concentrations at or above 5 microM, and by phenytoin at 100 microM, without significant affect on nerve conduction time, AP magnitude (inferred from extracellular field), and AP duration. The effect of both drugs appeared solely postsynaptic because hypoxia-induced catecholamine release in the carotid body was not altered by either drug. The respiratory response of unanesthetized, unrestrained 2-wk-old rats to acute hypoxia (12% inspired O(2) fraction), which was measured with whole body plethysmography, was significantly reduced after treatment with riluzole (2 mg/kg ip) and phenytoin (20 mg/kg ip). We conclude that I(NaP) is present in chemoreceptor afferent neurons and serves an important role in peripheral chemoreceptor function and, hence, in the ventilatory response to hypoxia.

Peripheral Chemoreceptors: Function and Plasticity of the Carotid Body

“…Thus, it is worth noting that a role for nonchemical, electrical synapses has been forwarded (248) and also that the entire premise of classical neurotransmission in the carotid body has been questioned (218, 811). Donnelly (218) observed that afferent action potentials appear not to be dependent upon synaptic depolarizing potentials in the nerve terminals, as would be expected, but instead, are linked to a process endogenous to the nerve terminals themselves whereby an increased variability in excitability is brought about by channel noise, developed by a persistent Na + current (263). In this proposal, chemicals released from type I cells during stimulation would act to modulate rather than generate the nerve terminal excitability and afferent action potentials should therefore persist in the absence of type I cells.…”

Autism throughout genetics: Perusal of the implication of ion channels

“…A recent study showed that the phenotypic signs of ASD induced by VAP exposure in rats can be significantly improved or recovered by the administration of vitamin D in early stages of development (Du, Zhao, Duan, & Li, 2017). In addition, it has been demonstrated that persistent Na + current is responsible for hypoxia in neurons leading to neuronal damages (Faustino & Donnelly, 2006). In fact, the persistence of Na + currents leads to the increased activity of Na + /Ca 2+ exchangers in neurons, itself resulting in an increase in Ca 2+ cytoplasmic concentration (Faustino & Donnelly, 2006).…”

“…In addition, it has been demonstrated that persistent Na + current is responsible for hypoxia in neurons leading to neuronal damages (Faustino & Donnelly, 2006). In fact, the persistence of Na + currents leads to the increased activity of Na + /Ca 2+ exchangers in neurons, itself resulting in an increase in Ca 2+ cytoplasmic concentration (Faustino & Donnelly, 2006). In order to correct this situation, it has been proposed that an increase in Na + influx into cells prevents trauma in the nervous system (Ates et al., 2007).…”

The influence of chronic hypoxia upon chemoreception

“…Donnelly recently showed that a persistent Na + current (I NaP ), which is sensitive to riluzole and tetrodotoxin and present only on afferent nerves, plays a critical role in carotid body O 2 -sensitivity (Faustino and Donnelly, 2006). Chemosensitivity in the afferent nerve endings is an attractive hypothesis that might explain experimental results such as the recovery of chemosensitivity in the carotid sinus nerve after removal of the carotid body (Mitchell et al, 1972), and the large variation in effects of a given neurotransmitter or neuromodulators on chemoreception between species (see below).…”