We have begun to identify and characterize genes that are differentially expressed with low magnesium. One of these sequences conformed to the ancient conserved domain protein, ACDP2. Real-time reverse transcription polymerase chain reaction of mRNA isolated from distal epithelial cells cultured in low magnesium media relative to normal media and in kidney cortex of mice maintained on low magnesium diets compared to those animals consuming normal diets confirmed that the ACDP2 transcript is responsive to magnesium. Mouse ACDP2 was cloned from MDCT cells, expressed in Xenopus laevis oocytes, and studied with two-electrode voltage-clamp studies. When expressed in oocytes, ACDP2 mediates saturable Mg²⁺ uptake with a Michaelis constant of 0.56 ± 0.05 mM. Transport of Mg²⁺ by ACDP2 is rheogenic, voltage-dependent, and is not coupled to Na⁺ or Cl^- ions. Expressed ACDP2 transports a range of divalent cations: Mg²⁺, Co²⁺, Mn²⁺, Sr²⁺, Ba²⁺, Cu²⁺, and Fe²⁺; accordingly it is a divalent cation transporter with wide substrate selectivity. The cations Ca²⁺, Cd²⁺, Zn²⁺ and Ni²⁺ did not induce currents and only Zn²⁺ effectively inhibited transport. The ACDP2 transcript is abundantly present in kidney, brain, heart with lower amounts in liver, small intestine and colon. Moreover, ACDP2 mRNA is upregulated with magnesium deficiency particularly in the distal convoluted tubule cells, kidney, heart, and brain. These studies suggest that ACDP2 may provide a regulated transporter for Mg²⁺ and other divalent cations in epithelial cells.