["The Journal of Physiology, Volume 604, Issue 7, Page 2816-2844, 1 April 2026. ", "\nAbstract figure legend 6‐Methylsulfinylhexyl isothiocyanate (6‐MSITC, hexaraphane), a wasabi sulfinyl compound, activates intracellular carbonic anhydrase (CA)‐mediated sequential HCO3−, Na+, H+ and Ca2+ transport through an activation axis involving HCO3−‐transporting solute carrier family 4 (SLC4As), the Na+–H+ exchanger (NHE), the Na+–Ca2+ exchanger (NCX) and plasma membrane Ca2+‐ATPase (PMCA). 6‐MSITC exhibits a strong ability to induce reactionary dentin formation via CA‐mediated SLC4A–NHE–NCX–PMCA coupling, making it a promising and potent candidate for novel dentin‐regenerative therapy.\n\n\n\n\n\n\n\n\n\nAbstract\nCa2+‐permeable transient receptor potential channels, which play an important role in the developmental/reactionary dentinogenesis by odontoblasts, are sensitive to wasabi sulfinyls. We investigated the effects of the wasabi sulfinyls 6‐methylsulfinylhexyl isothiocyanate (6‐MSITC) and its eight derivatives on ion transport mechanisms which promote mineralisation by odontoblasts. 6‐MSITC significantly increased the mineralisation efficiency in cultured odontoblasts, and we also observed a significant increase in medium pH. Inhibitors of carbonic anhydrase (CA) and plasma membrane Ca2+‐ATPase (PMCA) significantly reduced 6‐MSITC‐induced mineralisation. Odontoblasts expressed the HCO3−‐transporting solute carrier family 4 (SLC4A) members SLC4A1, SLC4A2, SLC4A3, SLC4A4, SLC4A8 and SLC4A9, as well as CA I and CA II. 6‐MSITC enhanced reactionary dentinogenesis beneath the cavities prepared on rat mandibular first molars. We recorded 6‐MSITC‐induced outward currents, which were suppressed by inhibitors of CA, Na+–H+ exchanger (NHE), and Na+–Ca2+ exchanger (NCX). These results indicated that 6‐MSITC has a strong ability to form reactionary dentin by activating or upregulating intracellular CA and electrically neutral HCO3−/H+ transport via SLC4As/NHE. Exchanging Na+ with H+ using NHE resulted in the reversal of the transmembrane Na+ gradient. This activated the Ca2+ influx mode of NCX, and the subsequent accumulation of intracellular Ca2+ was then extruded by PMCA activity to produce reactionary dentin. Thus, 6‐MSITC activates CA‐mediated SLC4As–NHE–NCX–PMCA coupling and is useful in dentin regenerative medicine.\n\n\n\n\n\n\n\n\n\nKey points\n\nCa2+ signalling in odontoblasts plays an important role not only in developmental/reactionary dentinogenesis, but also in the generation of dentinal (tooth) pain.\nThe wasabi sulfinyls including 6‐methylsulfinylhexyl isothiocyanate (6‐MSITC) promote mineralisation by odontoblasts and significantly increase pH in medium with cultured odontoblasts.\nWe showed that 6‐MSITC has a strong ability to form reactionary dentin through the upregulation and activation of intracellular carbonic anhydrase (CA) and electrically neutral HCO3−/H+ transport by members of the HCO3−‐transporting solute carrier family 4 (SLC4As) and Na+‐H+ exchanger (NHE).\nNa+ accumulation by NHE activity resulted in the reversal of the transmembrane Na+ gradient. This activated the Ca2+ influx mode of the Na+–Ca2+ exchanger (NCX), resulting in the accumulation of intracellular Ca2+. It was then extruded using plasma membrane Ca2+‐ATPase (PMCA) to produce reactionary dentin.\n6‐MSITC activates CA‐mediated SLC4As–NHE–NCX–PMCA coupling and is useful in dentin regenerative medicine.\n\n\n"]