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Summary: STIM1 in the endoplasmic reticulum and CRACM1 in the plasma membrane are essential molecular components for controlling the store-operated CRAC current . CRACM1 proteins multimerize and bind STIM1 , and the combined overexpression of STIM1 and CRACM1 reconstitutes amplified CRAC currents . Mutations in CRACM1 determine the selectivity of CRAC currents, demonstrating that CRACM1 forms the CRAC channel''s ion-selective pore , but the CRACM1 homologs CRACM2 and CRACM3 are less well characterized . Here, we show that both CRACM2 and CRACM3, when overexpressed in HEK293 cells stably expressing STIM1, potentiate ICRAC to current amplitudes 15–20 times larger than native ICRAC. A nonconducting mutation of CRACM1 (E106Q) acts as a dominant negative for all three CRACM homologs, suggesting that they can form heteromultimeric channel complexes. All three CRACM homologs exhibit distinct properties in terms of selectivity for Ca2+ and Na+, differential pharmacological effects in response to 2-APB, and strikingly different feedback regulation by intracellular Ca2+. Each of the CRAC channel proteins'' specific functional features and the potential heteromerization provide for flexibility in shaping Ca2+ signals, and their characteristic biophysical and pharmacological properties will aid in identifying CRAC-channel species in native cells that express them. [Copyright &y& Elsevier]