Fluoride ions are highly reactive, and their incorporation in forming dental enamel at low concentrations promotes mineralization. In contrast, excessive fluoride intake causes dental fluorosis, visually recognizable enamel defects that can increase the risk of caries. To investigate the molecular bases of dental fluorosis, we analyzed the effects of fluoride exposure in enamel cells to assess its impact on Ca²⁺ signaling. Primary enamel cells and an enamel cell line (LS8) exposed to fluoride showed decreased internal Ca²⁺ stores and store-operated Ca²⁺ entry (SOCE). RNA-sequencing analysis revealed changes in gene expression suggestive of endoplasmic reticulum (ER) stress in fluoride-treated LS8 cells. Fluoride exposure did not alter Ca²⁺ homeostasis or increase the expression of ER stress–associated genes in HEK-293 cells. In enamel cells, fluoride exposure affected the functioning of the ER-localized Ca²⁺ channel IP₃R and the activity of the sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump during Ca²⁺ refilling of the ER. Fluoride negatively affected mitochondrial respiration, elicited mitochondrial membrane depolarization, and disrupted mitochondrial morphology. Together, these data provide a potential mechanism underlying dental fluorosis.

Background: Chronic ethanol (EtOH) consumption has been associated with deleterious effects on the cardiovascular system by abnormal calcium (Ca2+) handling. Store-operated Ca2+ entry (SOCE) is related to cardiovascular remodeling which leads to the hypertension development, and the coupling between STIM-1 (ER Ca2+ sensor) and Orai-1 (channel pore) is a key mechanism to control SOCE through of store-operated Ca2+ channels (SOCCs). However, the role of STIM-1/Orai-1-mediated SOCE and its cross-talk with EtOH-triggered vascular remodeling and hypertension remain poorly understood. We address this subject in the present study by evaluating how chronic EtOH consumption induces alterations in Ca2+ handling via SOCE. Methods: Male Wistar Kyoto (WKY) and Spontaneously Hypertensive (SHR) rats were subjected to the intake of increasing EtOH concentrations (5-20%, for 30 days). Systolic blood pressure (SBP) and EtOH concentration were measured; cardiovascular remodeling was assessed by histomorphometry; and function/ expression of STIM-1/Orai-1-mediated Ca2+ influx were evaluated by isometric contraction and western blot experiments. Results: Compared to the WKY-Control, our results show that: (1) chronic EtOH consumption caused a significant elevation of SBP in both strains; (2) cardiac hypertrophy and hypertrophic aortic wall remodeling much more pronounced in WKY-EtOH; (3) decreased capacity of ER to store and release Ca2+; (4) increased STIM-1/Orai-1-mediated SOCCs activation, which was selectively inhibited by YM-58483; and (5) increased expression of STIM-1 in WKY-EtOH and SHR-Control rats. Conclusion: These findings suggest that hypertrophic aortic remodeling and abnormal contraction triggered mainly by Ca2+ overload via STIM-1/Orai-1-mediated SOCE through SOCCs are involved hypertension developed by EtOH consumption.

Oral cancer causes pain associated with cancer progression. We report here that the function of the Ca ²⁺ channel ORAI1 is an important regulator of oral cancer pain. ORAI1 was highly expressed in tumor samples from patients with oral cancer, and ORAI1 activation caused sustained Ca ²⁺ influx in human oral cancer cells. RNA-seq analysis showed that ORAI1 regulated many genes encoding oral cancer markers such as metalloproteases (MMPs) and pain modulators. Compared with control cells, oral cancer cells lacking ORAI1 formed smaller tumors that elicited decreased allodynia when inoculated into mouse paws. Exposure of trigeminal ganglia neurons to MMP1 evoked an increase in action potentials. These data demonstrate an important role of ORAI1 in oral cancer progression and pain, potentially by controlling MMP1 abundance.

Hypertension and diabetes development had been characterized as idiopathic disorders tightly interconnected, and therefore it is essential to understand how the functionality of neurohormonal pathways are involved in both diseases. Hypertensive and diabetic patients have shown increased systolic blood pressure (SBP), oxidative stress, vascular hypertrophy, and remodeling. It is well established that the long-term consumption of red wine and/or polyphenol-stilbene causes cardioprotective and antihypertensive effects; however, some functions remain unrevealed. Downstream pathways such as reactive oxygen species (ROS), sympathoadrenal axis represented by β₁-adrenoceptors, and renin–angiotensin system via angiotensin-II receptors critically contribute to hypertension development.

Plasma membrane protein channels provide a passageway for ions to access the intracellular milieu. Rapid entry of calcium ions into cells is controlled mostly by ion channels, while Ca²⁺-ATPases and Ca²⁺ exchangers ensure that cytosolic Ca²⁺ levels ([Ca²⁺]_cyt) are maintained at low (~100 nM) concentrations. Some channels, such as the Ca²⁺-release-activated Ca²⁺ (CRAC) channels and voltage-dependent Ca²⁺ channels (CACNAs), are highly Ca²⁺-selective, while others, including the Transient Receptor Potential Melastatin (TRPM) family, have broader selectivity and are mostly permeable to monovalent and divalent cations. Activation of CRAC channels involves the coupling between ORAI1-3 channels with the endoplasmic reticulum (ER) located Ca²⁺ store sensor, Stromal Interaction Molecules 1-2 (STIM1/2), a pathway also termed store-operated Ca²⁺ entry (SOCE). The TRPM family is formed by 8 members (TRPM1-8) permeable to Mg²⁺, Ca²⁺, Zn²⁺ and Na⁺ cations, and is activated by multiple stimuli. Recent studies indicated that SOCE and TRPM structure-function are interlinked in some instances, although the molecular details of this interaction are only emerging. Here we review the role of TRPM and SOCE in Ca²⁺ handling and highlight the available evidence for this interaction.