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Calcification of the enamel matrix via hydroxyapatite (HAP) maturation requires pH cycling to be tightly regulated through the neutralization of protons released during HAP synthesis. We found that\n                    <jats:italic>Gpr115<\/jats:italic>\n                    , which responds to changes in extracellular pH, plays an important role in enamel formation.\n                    <jats:italic>Gpr115<\/jats:italic>\n                    \u2010deficient mice show partial enamel hypomineralization, suggesting that other pH\u2010responsive molecules may be involved. In this study, we focused on the role of\n                    <jats:italic>Gpr111\/Adgrf2<\/jats:italic>\n                    , a duplicate gene of\n                    <jats:italic>Gpr115<\/jats:italic>\n                    , in tooth development.\n                    <jats:italic>Gpr111<\/jats:italic>\n                    was highly expressed in mature ameloblasts.\n                    <jats:italic>Gpr111<\/jats:italic>\n                    \u2010KO mice showed enamel hypomineralization. Dysplasia of enamel rods and high carbon content seen in\n                    <jats:italic>Gpr111<\/jats:italic>\n                    \u2010deficient mice suggested the presence of residual enamel matrices in enamel. Depletion of\n                    <jats:italic>Gpr111<\/jats:italic>\n                    in dental epithelial cells induced the expression of ameloblast\u2010specific protease,\n                    <jats:italic>kallikrein\u2010related peptidase 4<\/jats:italic>\n                    (\n                    <jats:italic>Klk4<\/jats:italic>\n                    ), suggesting that\n                    <jats:italic>Gpr111<\/jats:italic>\n                    may act as a suppressor of\n                    <jats:italic>Klk4<\/jats:italic>\n                    expression. Moreover, reduction of extracellular pH to 6.8 suppressed the expression of\n                    <jats:italic>Gpr111<\/jats:italic>\n                    , while the converse increased\n                    <jats:italic>Klk4<\/jats:italic>\n                    expression. Such induction of\n                    <jats:italic>Klk4<\/jats:italic>\n                    was synergistically enhanced by\n                    <jats:italic>Gpr111<\/jats:italic>\n                    knockdown, suggesting that proper enamel mineralization may be linked to the modulation of\n                    <jats:italic>Klk4<\/jats:italic>\n                    expression by\n                    <jats:italic>Gpr111<\/jats:italic>\n                    . Furthermore, our in vitro suppression of\n                    <jats:italic>Gpr111<\/jats:italic>\n                    and\n                    <jats:italic>Gpr115<\/jats:italic>\n                    expression indicated that their suppressive effect on calcification was additive. These results suggest that both\n                    <jats:italic>Gpr111<\/jats:italic>\n                    and\n                    <jats:italic>Gpr115<\/jats:italic>\n                    respond to extracellular pH, contribute to the expression of proteolytic enzymes, and regulate the pH cycle, thereby playing important roles in enamel formation.\n                  <\/jats:p>","DOI":"10.1096\/fj.202202053r","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T03:56:07Z","timestamp":1679025367000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Deficiency of G protein\u2010coupled receptor\n                    <i>Gpr111\/Adgrf2<\/i>\n                    causes enamel hypomineralization in mice by alteration of the expression of kallikrein\u2010related peptidase 4 (\n                    <i>Klk4<\/i>\n                    ) during\n                    <scp>pH<\/scp>\n                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