Provided are methods of screening test compounds for the ability to alter calcium homeostasis in mammalian cells by experimentally determining if a compound affects CALHM1, CALHM2, or CALHM3 expression or activity. Additionally provided are methods of screening a test compound for the ability to inhibit ERK 1/2 phosphorylation in a mammalian cell. Further provided are methods of screening a test compound for the ability to inhibit amyloid-beta peptide accumulation in a mammalian cell or biological fluid, methods of screening for a test compound that may affect Alzheimers disease and methods of determining the likelihood that a subject will be diagnosed with Alzheimers disease. Also provided are isolated and purified mammalian CALHM proteins, vectors comprising a nucleic acid sequence encoding the CALHM1, CALHM2, and CALHM3 proteins, and mammalian cells transfected with the vectors. Additionally, methods of affecting Ca2+ levels in a mammalian cell are provided.
