N-geranyl cyclopropyl-carboximide modulates salty and umami taste in humans and animal models

Abstract

Dewis ML, Phan TH, Ren ZJ, Meng X, Cui M, Mummalaneni S, Rhyu MR, DeSimone JA, Lyall V. N-geranyl cyclopropylcarboximide modulates salty and umami taste in humans and animal models. J Neurophysiol 109: 1078 -1090, 2013. First published December 5, 2012; doi:10.1152/jn.00124.2012.-Effects of N-geranyl cyclopropylcarboxamide (NGCC) and four structurally related compounds (Ncyclopropyl E2,Z6-nonadienamide, N-geranyl isobutanamide, N-geranyl 2-methylbutanamide, and allyl N-geranyl carbamate) were evaluated on the chorda tympani (CT) nerve response to NaCl and monosodium glutamate (MSG) in rats and wild-type (WT) and TRPV1 knockout (KO) mice and on human salty and umami taste intensity. NGCC enhanced the rat CT response to 100 mM NaCl ϩ 5 M benzamil (Bz; an epithelial Na ϩ channel blocker) between 1 and 2.5 M and inhibited it above 5 M. N-(3-methoxyphenyl)-4-chlorocinnamid (SB-366791, a TRPV1t blocker) inhibited the NaClϩBz CT response in the absence and presence of NGCC. Unlike the WT mice, no NaClϩBz CT response was observed in TRPV1 KO mice in the absence or presence of NGCC. NGCC enhanced human salt taste intensity of fish soup stock containing 60 mM NaCl at 5 and 10 M and decreased it at 25 M. Rat CT responses to NaClϩBz and human salt sensory perception were not affected by the above four structurally related compounds. Above 10 M, NGCC increased the CT response to MSGϩBzϩSB-366791 and maximally enhanced the response between 40 and 60 M. Increasing taste cell Ca 2ϩ inhibited the NGCC-induced increase but not the inosine monophosphate-induced increase in glutamate response. Addition of 45 M NGCC to chicken broth containing 60 mM sodium enhanced the human umami taste intensity. Thus, depending upon its concentration, NGCC modulates salt taste by interacting with the putative TRPV1t-dependent salt taste receptor and umami taste by interacting with a Ca 2ϩ

TRPM5-dependent amiloride- and benzamil-insensitive NaCl chorda tympani taste nerve response

“…In our studies, putative TRPV1/ TRPV1t agonists and antagonists show similar effects in WT mice, PLC␤ 2 KO mice, Sprague-Dawley rats, P rats, and NP rats (6). The nonpungent agonists of TRPV1/TRPV1t-dependent Bz-insensitive NaCl CT responses modulate human salt taste in a biphasic manner (11,20). Thus the effects of TRPV1/TRPV1t agonists/antagonists are strain-and agonistindependent.…”

“…In two-bottle 48-h preference tests, a "kokumi"-taste active peptide produced biphasic effects on NaCl preference in C57BL/6J mice and on the Bz-insensitive NaCl CT response (41). MRPs and N-geranylcyclopropylcarboximide produced biphasic effects on the Bz-insensitive NaCl CT response in rodents and also on salt sensory evaluation in humans (11,20). However, significant behavioral differences from WT mice for high concentrations of NaCl and KCl were observed only in double-mutant mice in which polycystic kidney disease 2-like 1-expressing cells were silenced and TRPM5 was mutated (35).…”

“…1), Sprague-Dawley rats, alcohol-preferring (P) rats, and alcohol-non-preferring (NP) rats (6,26). In addition, several low-affinity blockers that inhibit the Bz-insensitive NaCl CT response in the micromolarto-millimolar range include RTX, capsaicin, cetylpyridinium chloride, Maillard reacted peptides (MRPs), N-geranylcyclopropylcarboximide, ethanol, and nicotine (6,11,20,26,27,29,30,40,41,48). Our whole nerve data are supported by the effect of TRPV1 agonists on single CT nerve fibers.…”

“…Control stimuli consisting of 300 mM NH 4Cl and 300 mM NaCl applied at the beginning and end of the experiment were used to assess preparation stability (31,32). As in our previous studies, the control responses did not differ by more than 2-5% at the beginning and end of the experiment (11,48). The stimulus series used in the CT experiments to generate the relationship between RTX concentration and the magnitude of the NaCl ϩ Bz CT response was as follows: R ¡ 300 mM NH 4Cl ¡ R ¡ 300 mM NaCl ¡ R ¡ 100 mM NaCl ¡ R ¡ (100 mM NaCl…”

Selective Activation of hTRPV1 by N-Geranyl Cyclopropylcarboxamide, an Amiloride-Insensitive Salt Taste Enhancer

“…At the concentrations that NGCC inhibited the Bz-insensitive NaCl CT response in rodents, it produced a salt masking effect in human psychophysical tests. NGCC did not enhance the Bz-sensitive NaCl CT response [27]. In our earlier paper we did not have direct evidence that NGCC modulates the activity of TRPV1 and ENaC is insensitive to it.…”