Abstract
The effects of small molecule ENaC activators N,N,N-trimethyl-2-((4-methyl-2-((4-methyl-1H-indol-3-yl)thio)pentanoyl)oxy)ethanaminium iodide (Compound 1) and N-(2-hydroxyethyl)-4-methyl-2-((4-methyl-1H-indol-3-yl)thio)pentanamide (Compound 2), were tested on the benzamil (Bz)-sensitive NaCl chorda tympani (CT) taste nerve response under open-circuit conditions and under ±60 mV applied lingual voltage-clamp, and compared with the effects of known physiological activators (8-CPT-cAMP, BAPTA-AM, and alkaline pH), and an inhibitor (ionomycin+Ca2+) of ENaC. The NaCl CT response was enhanced at −60 mV and suppressed at +60 mV. In every case the CT response (r) versus voltage (V) curve was linear. All ENaC activators increased the open-circuit response (ro) and the voltage sensitivity (κ, negative of the slope of the r versus V curve) and ionomycin+Ca2+ decreased ro and κ to zero. Compound 1 and Compound 2 expressed a sigmoidal-saturating function of concentration (0.25–1 mM) with a half-maximal response concentration (k) of 0.49 and 1.05 mM, respectively. Following treatment with 1 mM Compound 1, 8-CPT-cAMP, BAPTA-AM and pH 10.3, the Bz-sensitive NaCl CT response to 100 mM NaCl was enhanced and was equivalent to the Bz-sensitive CT response to 300 mM NaCl. Plots of κ versus ro in the absence and presence of the activators or the inhibitor were linear, suggesting that changes in the affinity of Na+ for ENaC under different conditions are fully compensated by changes in the apical membrane potential difference, and that the observed changes in the Bz-sensitive NaCl CT response arise exclusively from changes in the maximum CT response (rm). The results further suggest that the agonists enhance and ionomycin+Ca2+ decreases ENaC function by increasing or decreasing the rate of release of Na+ from its ENaC binding site to the receptor cell cytosol, respectively. Irrespective of agonist type, the Bz-sensitive NaCl CT response demonstrated a maximum response enhancement limit of about 75% over control value.
Highlights
In rats, about 70% of the chorda tympani (CT) taste nerve response to NaCl is due to Na+ influx through the amiloride- and benzamil (Bz)-sensitive epithelial Na+ channel (ENaC) expressed in the apical membrane of a subset of fungiform taste bud cells, and is associated with appetitive behavioral responses to low NaCl concentrations [1,2,3,4]
No significant effect of amiloride is observed on perceived salt taste intensity in human subjects even when tested at levels at approximately 300-fold above the IC50 for abc ENaC expressed in oocytes and equivalent to approximately 10-fold over the IC50 value for dbc ENaC expressed in oocytes [7,8,9]
The 8-CPT-cyclic adenosine monophosphate (cAMP) induced increase in the Bz-sensitive NaCl CT response was not observed when the rat tongue was treated with Rp-8-CPT-cAMP (Figure S1). These results suggest that cAMP-induced enhancement in the NaCl CT response is protein kinase A (PKA) dependent
Summary
About 70% of the chorda tympani (CT) taste nerve response to NaCl is due to Na+ influx through the amiloride- and benzamil (Bz)-sensitive epithelial Na+ channel (ENaC) expressed in the apical membrane of a subset of fungiform taste bud cells, and is associated with appetitive behavioral responses to low NaCl concentrations [1,2,3,4]. No significant effect of amiloride is observed on perceived salt taste intensity in human subjects even when tested at levels at approximately 300-fold above the IC50 for abc ENaC expressed in oocytes and equivalent to approximately 10-fold over the IC50 value for dbc ENaC expressed in oocytes [7,8,9]. These differences reflect the inherently different properties of hENaC and rENaC or mENaC and their relative contributions to salt taste sensing in humans and rodent models, respectively
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