Pure zyxwvutsrqpo & zyxwvutsrq Appl. Chem., zyxwvutsr Vol. 69, No. 4, pp. 701-708, 1997. Printed in Great Britain. (0 1997 IUPAC Receptors that mediate sweetness: Inferences from biochemical, electrophysiological and psychophysicaldata Susan S. Schiffman Department of Psychiatry, Duke University Medical Center, zyx Box 3259, Durham, NC 27705 USA Abstract: Identification, isolation, and characterization of taste receptors for sweet compounds have not yet been accomplished due to inadequate biochemical techniques appropriate for studying receptor binding in gustation. However, a series of biochemical, electrophysiological, and psychophysical studies suggest that proteinaceous receptors coupled to the G-protein/adenylate cyclase second messenger cascade mediate sweet taste for some compounds. Other second messenger systems (e.g. the phosphatidyl inositol system) as well as ion channels and non-receptor mechanisms may also be involved. There is ample evidence that multiple types of sweet receptors are required to transduce signals for the many chemical classes of compounds that taste sweet: e.g. low molecular weight carbohydrates, aminoacyl sugars, amino acids, peptides, proteins, terpenoids, chlorinated hydrocarbons, halogenated sugars, N-sulfonyl amides, sulfamates, polyketides, anilines, and ureas. Evidence for multiple receptors comes from a variety of studies including: 1) use of sweetness inhibitors (e.g. gymnemic acid or phenoxyalkanoic acid compounds), 2) electrophysiological recordings using modifiers of second messenger systems, zyxwvuts 3) cross-adaptation studies, 4) sweetener mixtures that produce synergy, and 5) structure-activity studies combined with molecular modeling. When adequate biochemical techniques are finally achieved for isolating and characterizing sweet receptor proteins, the rational and systematic design of sweeteners by computer will replace serendipity in the discovery of new sweetener compounds. SWEET-TASTE RECEPTORS AND THE ADENYLATE CYCLASE SYSTEM The search for taste receptors that bind sweeteners has not been as successful as the pursuit of neurotransmitter and hormone receptors. In fact, no receptor for sweet taste has yet been isolated and characterized. Isolation of sweet taste receptors is limited by the low affinity of tastants for receptors as well as the physiology of the gustatory system. Although the isolation of sweetener receptors has proven difficult, current consensus is that the sweet taste response is mediated by taste cell surface receptors that utilize the adenylate cyclase system as a second messenger system. The adenylate cyclase system, which is also the cellular signaling system for many hormones, involves the cascade of events shown in Figure 1. The sweetener molecule (agonist) binds to a receptor which transmits a signal via the guanine nucleotide-binding protein (G protein) resulting in activation of adenylate cyclase. Adenylate cyclase then induces hydrolysis of ATP to cAMP which leads to activation of the phosphorylating enzyme known as protein kinase A. The activated kinase then phosphorylates an ion channel in the taste cell membrane leading to depolarization of the taste cell. The validity of the model in Figure 1 for sweet taste transduction is supported by biochemical investigations that have established the existence and activation of components of the adenylate system in taste buds including adenylate cyclase (ref. 1-4), cAMP phosphodiesterase (ref. 33, cAMP (6), and CAMP-dependent kinase zyx (7). Certain sweeteners including sucrose and saccharin cause a stimulation in adenylate cyclase activity leading to elevated levels of cAMP (6). 701