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 (PLC2) 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 PLC2 and transient-receptor potential receptor M5 (TRPM5) are necessary (8, 9), but the molecular mechanism by which PLC2 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 PLC2 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 ...