Some sweet and bitter tastants stimulate inhibitory pathway of adenylyl cyclase via melatonin and α₂-adrenergic receptors in Xenopus laevis melanophores

Abstract

Zubare-Samuelov, Meirav, Irena Peri, Michael Tal, Mark Tarshish, Andrew I. Spielman, and Michael Naim. Some sweet and bitter tastants stimulate inhibitory pathway of adenylyl cyclase via melatonin and ␣ 2-adrenergic receptors in Xenopus laevis melanophores. Am J Physiol Cell Physiol 285: C1255-C1262, 2003. First published July 2, 2003 10.1152/ajpcell.00149.2003.-The sweeteners saccharin, D-tryptophan, and neohesperidin dihydrochalcone (NHD) and the bitter tastant cyclo(Leu-Trp) stimulated concentrationdependent pigment aggregation in a Xenopus laevis melanophore cell line similar to melatonin. Like melatonin, these tastants inhibited (by 45-92%) cAMP formation in melanophores; pertussis toxin pretreatment almost completely abolished the tastant-induced cAMP inhibition, suggesting the involvement of the inhibitory pathway (Gi) of adenylyl cyclase. The presence of luzindole (melatonin receptor antagonist) almost completely abolished the inhibition of cAMP formation induced by saccharin, D-tryptophan, and cyclo(Leu-Trp) but only slightly affected the inhibitory effect of NHD. In contrast, the presence of an ␣2-adrenergic receptor antagonist, yohimbine, almost completely abolished the inhibition of cAMP formation induced by NHD but had only a minor effect on that induced by the other tastants. Thus saccharin, D-tryptophan, and cyclo(Leu-Trp) are melatonin receptor agonists whereas NHD is an ␣2-adrenergic receptor agonist, but both pathways lead to the same transduction output and cellular response. Formation of D-myo-inositol 1,4,5-trisphosphate (IP3) in melanophores was reduced (15-58%, no concentration dependence) by saccharin, D-tryptophan, and cyclo(Leu-Trp) stimulation but increased by NHD stimulation. Tastant stimulation did not affect cGMP. Although some of the above tastants were found to be membrane permeant, their direct activation of downstream transduction components in this experimental system is questionable. MT1 and MT2 melatonin receptor mRNAs were identified in rat circumvallate papilla taste buds and nonsensory epithelium, suggesting the occurrence of MT1 and MT2 receptors in these tissues. Melatonin stimulation reduced the cellular content of cAMP in taste cells, which may or may not be related to taste sensation. pigment aggregation; adenosine 3Ј,5Ј-cyclic monophosphate; D-myo-inositol 1,4,5-trisphosphate; permeation THE NEWLY DISCOVERED G protein-coupled taste receptors (GPCRs; Refs. 4,7,20,21,27) are likely to play a major role in the exertion of sweet and bitter tastant taste stimulation. Proposed pathways for the downstream transduction of sweet taste include increases in cAMP (40, 41), and more recently cGMP (15), in response to stimulation by sugars and in D-myo-inositol 1,4,5-trisphosphate (IP 3 ) in response to nonsugar stimulation (2). Apparently, bitter taste transduction involves stimulation of the PLC-IP 3 pathway, a reduction in cAMP, and an increase in cGMP (32,34,38). Very recently (46), sweet, bitter, and amino acid tastes, but not sour and salty tastes, were proposed to be trans...

Artificial sweeteners and salts producing a metallic taste sensation activate TRPV1 receptors

“…Also, along these non-TRPV1 receptor mechanisms, we note that amphipathic molecules have been shown to open a variety of initially closed ion channels and thus may open channels in TRCs (6,33). Finally, in Xenopus laevis melanophores, it has been shown that saccharin can activate the melatonin receptor, which also is expressed in rat circumvallate papille taste buds (57).…”

“…Initially, we consider how AS may affect the taste system via transduction pathways in TRCs. The elegant work of Naim and colleagues (40,57,58) provides a rationale for the lingering aftertaste of AS that does not require the activation of TRPV1 channels. They showed that AS, like saccharin, can diffuse across the plasma membrane of the TRCs and accumulate, at relatively high concentrations, in the cytoplasm where they may interact with and subsequently delay signal-termination components located downstream of the sweet or bitter responding GPCRs (depending on the concentration).…”

“…This shift has been explained by the activation at low concentrations of sweet tastant-sensing G protein-coupled receptors (GPCRs) T1R2/ T1R3 (23) and at higher concentrations, the activation of the bitter tastant sensing GPCRs, T2R43, and T2R44 for saccharin and acesulfame-K (21). Other taste sensations related to the aftertaste elicited by artificial sweeteners have been attributed to their diffusion into taste receptor cells where they can alter intracellular signaling pathways (37,38,40,57). A recent psychophysical study showed that it is sometimes difficult to distinguish between the bitterness caused by quinine and the irritating sensation produced by capsaicin, the principal pungent ingredient in chili peppers that activates TRPV1 receptors (24).…”

“…Peptide toxins from tarantula venom also activate TRPV1 receptors (45). As the capsaicin binding site is on the cytoplasmic surface of TRPV1 (17,18), all of these organic molecules must either be synthesized intracellularly or be able to permeate into the lingual epithelia, where they could diffuse into TRCs (40,57,58) or nerve terminals (4,15) and eventually activate TRPV1 receptors. TRPV1 receptors have also been shown to be directly activated on the extracellular side by high concentrations of Ca 2ϩ and Mg 2ϩ (1).…”

Stimulus-Dependent Effects of Temperature on Bitter Taste in Humans

“…However, such effects are plausible based on evidence that greater structural flexibility in CGRP proteins, which is required for ligand binding and allostery, is associated with greater thermal instability (Vihinen 1987;Yuan et al 2005). It is also not yet certain that hT2R receptors are the sole transduction pathway for bitter taste in humans (Zubare-Samuelov et al 2003;OliveiraMaia et al 2009). This remains an open question in part because cognate hT2R receptors have not been identified for several bitter substances that have been tested, including naringin (Meyerhof et al 2010).…”