Calcium is a key regulator of a broad range of biological functions and is also a key element in the composition of dental enamel. During the maturation stage of amelogenesis, Ca2+ requirements increase as enamel crystals expand in width and thickness. Calcium must reach the forming enamel layer but how this process is regulated in ameloblasts is poorly understood. The current model for Ca2+ transport in enamel focuses on the transcellular passage of Ca2+ via the entry, transit and extrusion steps. Whereas several works have reported on the transit and extrusion steps, only limited information is available for Ca2+ entry mechanisms into ameloblasts. In this grant proposal, I focus on the entry step by examining the role of the store-operated Ca2+ release-activated Ca2+ (CRAC) channels. CRAC channels comprise important Ca2+ influx mechanism in epithelial cells. Patients with mutations to CRAC channels (STIM1, ORAI1) present, in addition to immune system deficiencies, with hypocalcified amelogenesis imperfecta. My goal is to identify how Stim1 and Orai1 are involved in Ca2+ entry and how this process is regulated. Recent work by the PI indicates that Stim1, Orai1 as well as well as the Ca2+ signaling cholecystokinin (Cck) and the Cck inhibitor Rcan1 were identified as being significantly up-regulated in maturation. I have confirmed these results by qPCR, Western blot and IHC. Thus Ca2+ influx into ameloblasts via CRAC channels and how this process is regulated is important for the development of healthy enamel. Evidence contributed by the proposed grant application will help to better understand the systemic effects of CRAC function abrogation. This will also help medical practitioners in making decisions concerning dentist visits to patients with mutations to CRAC channels in order to prevent dental problems

Public Health Relevance

/Relevance to Public Health Calcium is critical for the normal biomineralization of enamel. Disruptions to calcium uptake by ameloblasts results in amelogenesis imperfecta. My goal is to analyze the function of calcium-store operated channels in enamel development.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wan, Jason
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
Other Basic Sciences
Schools of Dentistry
New York
United States
Zip Code
Nurbaeva, Meerim K; Eckstein, Miriam; Devotta, Arun et al. (2018) Evidence That Calcium Entry Into Calcium-Transporting Dental Enamel Cells Is Regulated by Cholecystokinin, Acetylcholine and ATP. Front Physiol 9:801
Lacruz, Rodrigo S (2017) Enamel: Molecular identity of its transepithelial ion transport system. Cell Calcium 65:1-7
Eckstein, Miriam; Vaeth, Martin; Fornai, Cinzia et al. (2017) Store-operated Ca2+entry controls ameloblast cell function and enamel development. JCI Insight 2:e91166
Nurbaeva, Meerim K; Eckstein, Miriam; Feske, Stefan et al. (2017) Ca2+ transport and signalling in enamel cells. J Physiol 595:3015-3039
Lacruz, Rodrigo S; Habelitz, Stefan; Wright, J Timothy et al. (2017) DENTAL ENAMEL FORMATION AND IMPLICATIONS FOR ORAL HEALTH AND DISEASE. Physiol Rev 97:939-993
Concepcion, Axel R; Vaeth, Martin; Wagner 2nd, Larry E et al. (2016) Store-operated Ca2+ entry regulates Ca2+-activated chloride channels and eccrine sweat gland function. J Clin Invest 126:4303-4318
Lacruz, Rodrigo S; Bromage, Timothy G; O'Higgins, Paul et al. (2015) Ontogeny of the maxilla in Neanderthals and their ancestors. Nat Commun 6:8996
Nurbaeva, M K; Eckstein, M; Snead, M L et al. (2015) Store-operated Ca2+ Entry Modulates the Expression of Enamel Genes. J Dent Res 94:1471-7
Lacruz, Rodrigo S; Feske, Stefan (2015) Diseases caused by mutations in ORAI1 and STIM1. Ann N Y Acad Sci 1356:45-79
Yin, Kaifeng; Lei, Yuejuan; Wen, Xin et al. (2015) SLC26A Gene Family Participate in pH Regulation during Enamel Maturation. PLoS One 10:e0144703

Showing the most recent 10 out of 15 publications