Abnormal Taste Perception in Mice Lacking the Type 3 Inositol 1,4,5-Trisphosphate Receptor

Abstract

Inositol 1,4,5-trisphosphate receptor (IP 3 R) is one of the important calcium channels expressed in the endoplasmic reticulum and has been shown to play crucial roles in various physiological phenomena. Type 3 IP 3 R is expressed in taste cells, but the physiological relevance of this receptor in taste perception in vivo is still unknown. Here, we show that mice lacking IP 3 R3 show abnormal behavioral and electrophysiological responses to sweet, umami, and bitter substances that trigger G-proteincoupled receptor activation. In contrast, responses to salty and acid tastes are largely normal in the mutant mice. We conclude that IP 3 R3 is a principal mediator of sweet, bitter, and umami taste perception and would be a missing molecule linking phospholipase C ␤2 to TRPM5 activation.Taste perception is a pivotal and primitive sensory system for survival in animals. By sensing taste, animals are provided with valuable information about foods (e.g. qualities and nature) and can choose the nutrient-rich foods necessary for living or avoid harmful and toxic substances. There are five taste categories (sweet, bitter, umami, sour, and salty), and recent studies have furthered our understanding of the molecular mechanisms of taste perception, especially for sweet, bitter, and umami tastes (1, 2).For perception of sweet, bitter, and umami taste, phospholipase C ␤2 (PLC␤2) 3 activation through G-protein-coupled receptor (sweet, T1R2 ϩ T1R3; umami, T1R1 ϩ T1R3; bitter, T2Rs) (1, 3-8) and the subsequent activation of PLC␤2 and transient-receptor potential receptor M5 (TRPM5) are necessary (8, 9), but the molecular mechanism by which PLC␤2 activation leads to TRPM5 in vivo is still unclear (2). Several reports have suggested the possible involvement of Ca 2ϩ , probably released from the intracellular stores, in the activation of TRPM5 in heterologously expressed cells (10 -14) and in taste cells (15); however this remains controversial (9). Because PLC␤2 activation actually leads to production of both IP 3 and diacylglycerol, it is an important issue to definitely determine, which is a major player for gustatory systems. To clarify whether IP 3 R is necessary for taste perception in vivo, we analyzed the taste signaling of IP 3 R-deficient mice in this study (16). We found that mice lacking IP 3 R3 showed altered taste recognition for sweet, bitter, and umami, whereas they were indistinguishable from wild-type (WT) mice in their recognition for salty and sour stimuli. However, they showed residual responses to high concentrations of sweets and bitter. Our data present the direct validation that IP 3 R3 is a key molecule in taste perception for sweet, bitter, and umami and also suggest the existence of IP 3 R3-independent taste signal transduction for recognition of high dose of these tastants. EXPERIMENTAL PROCEDURESMice-IP 3 R3-and IP 3 R2-deficient mice were generated as described previously (16), and the mice intercrossed with C57BL/6 mice at least twelve times were used. WT C57BL/6 mice were littermates or purchased from ...

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“…Correspondingly, no large reduction of behavioral and neural responses to US has also been reported in mice lacking gene(s) controlling downstream signaling molecules, such as G protein a subunit (Ga) gustducin and/or transducin, 30) type III inositol-1-4,5-triphosphate receptor (IP 3 R3) 31) and a cation channel, transient receptor potential M5 channel (TRPM5). 32,33) Figure 1 shows concentration-response curves for MPG and mixture of MPG and IMP (MPGϩIMP) obtained from T1R3-, IP 3 R3-, TRPM5-KO mice and their wild type counterparts with the same C57BL genetic backgrounds.…”

“…40) Binding of IP 3 to IP 3 R3 leads to Ca 2ϩ release from intracellular stores which activates TRPM5 channels. 31) Activation of TRPM5 leads to Na ϩ entry, membrane depolarization and generation of action potential of taste cells. 32) Recent studies demon- It is noted that responses to the mixture are significantly lower than that for the sum of responses to each component alone.…”

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“…Correspondingly, no large reduction of behavioral and neural responses to umami compounds has been reported in mice lacking gene(s) controlling downstream signaling molecules, such as Gα-gustducin and/or transducin, 36) type III inositol-1-4,5-triphosphate receptor (IP 3 R3) 37) or the transient receptor potential M5 cation channel (TRPM5). 38,39) Concentration-response curves for MPG and the mixture of MPG and IMP (MPG + IMP) obtained from T1R3-, IP 3 R3-or TRPM5-KO mice and their wild type counterparts with the same C57BL genetic backgrounds indicate that these three lines of KO mice exhibited almost identical responsiveness to umami compounds with reduced CT nerve responses, no synergism, and little effect on GL nerve responses.…”

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“…The dissociated βγ subunits of the Ggust activate phospholipase C (PLCβ2), which hydrolyzes phosphatidylinositol bisphosphate (PIP 2 ) into diacylglycerol (DAG) and inositol trisphosphate (IP 3 ) (9). Subsequently, IP 3 activates the type III IP 3 receptor (IP 3 R3), leading to the release of Ca 2+ from intracellular stores (10). Rapid increases in [Ca 2+ ] i open basolaterally located transient receptor potential cation channel, subfamily M, member 5 (TRPM5) channels, leading to Na + influx, membrane depolarization, and generation of action potentials (11,12).…”