Calcium Transport in Specialized Dental Epithelia and Its Modulation by Fluoride

Abstract

Most cells use calcium (Ca2+) as a second messenger to convey signals that affect a multitude of biological processes. The ability of Ca2+ to bind to proteins to alter their charge and conformation is essential to achieve its signaling role. Cytosolic Ca2+ (cCa2+) concentration is maintained low at ~100 nM so that the impact of elevations in cCa2+ is readily sensed and transduced by cells. However, such elevations in cCa2+ must be transient to prevent detrimental effects. Cells have developed a variety of systems to rapidly clear the excess of cCa2+ including Ca2+ pumps, exchangers and sequestering Ca2+ within intracellular organelles. This Ca2+ signaling toolkit is evolutionarily adapted so that each cell, tissue, and organ can fulfill its biological function optimally. One of the most specialized cells in mammals are the enamel forming cells, the ameloblasts, which also handle large quantities of Ca2+. The end goal of ameloblasts is to synthesize, secrete and mineralize a unique proteinaceous matrix without the benefit of remodeling or repair mechanisms. Ca2+ uptake into ameloblasts is mainly regulated by the store operated Ca2+ entry (SOCE) before it is transported across the polarized ameloblasts to reach the insulated enamel space. Here we review the ameloblasts Ca2+ signaling toolkit and address how the common electronegative non-metal fluoride can alter its function, potentially addressing the biology of dental fluorosis.

PMCA Ca 2+ clearance in dental enamel cells depends on the magnitude of cytosolic Ca 2+

“…As discussed above, the main Ca 2+ influx pathway in ameloblasts is SOCE 6,25,38,60,61 . SOCE activation in ameloblasts elicits a robust increase in c Ca 2+ being significantly higher in maturation stage ameloblasts 4,25,38 .…”

“…As discussed above, the main Ca 2+ influx pathway in ameloblasts is SOCE. 6,25,38,60,61 SOCE activation in ameloblasts elicits a robust increase in c Ca 2+ being significantly higher in maturation stage ameloblasts. 4,25,38 These levels may exceed the Ca 2+ extrusion capacity of PMCAs but this has not been tested in ameloblasts to date.…”

“…In epithelial cells like the enamel forming ameloblasts, the cytosolic Ca 2+ ( c Ca 2+ ) concentration is tightly regulated by the balance between Ca 2+ influx (entry) and Ca 2+ extrusion (clearance) 1,2 . These processes in ameloblasts are mediated by a sophisticated machinery that first controls the uptake of Ca 2+ largely via the store‐operated Ca 2+ entry (SOCE) pathway 3‐6 formed by the stromal interacting proteins, STIM1/2, 7,8 and the pore of the channel comprised of the ORAI1‐3 proteins 9,10 . The Ca 2+ buffering and extrusion toolkit in this context is less known but plasma membrane Ca 2+ pumps and Ca 2+ exchangers, Ca 2+ ‐binding proteins and buffering by intracellular organelles have been reported 3,11‐15 .…”

Na+/Ca2+ exchange in enamel cells is dominated by the K+-dependent NCKX exchanger

“…S2 ). Conversely, the expression of NCKX4 is difficult to detect in the secretory stage and vastly increases in maturation, the stage when the Ca 2+ transport machinery is upregulated as crystals experience significant growth in thickness ( Costiniti et al, 2021 ; Hubbard, 2000 ; Lacruz, 2017 ; Lacruz et al, 2017 ; Smith, 1998 ).…”

Unraveled roles of Cav1.2 in proliferation and stemness of ameloblastoma

“…Indeed, various calcium channels involved in transporting Ca 2+ into milk are altered or modulated and may even be specific to breast cancer molecular subtypes. Similarly, dental epithelial cells, which are thought to be the origin of AM, possess many calcium channels required for tooth development [ 29 ].…”