Extracellular [H⁺]_o shifts the inward rectification of K_Ca2.3 to more depolarized potentials. Representative outside-out macropatch (A) K_Ca2.2 and (B) K_Ca2.3 currents in low K⁺ in the presence of increasing concentrations of [H⁺]_o. Decreasing extracellular pH inhibited both current subtypes, with a shift of inward rectification apparent for the K_Ca2.3 current. (C) Concentration–inhibition relationships for K_Ca2.2 and K_Ca2.3 currents measured at −60 mV in both low K⁺ (5 mM [K⁺]_o) and high K⁺ (150 mM [K⁺]), showing that both K_Ca2.2 and K_Ca2.3 currents were less sensitive to [H⁺]_o in low K⁺. Individual patches were fit with Eq. 1 to yield the following: K_Ca2.3, IC₅₀ = 269 ± 16 nM and pIC₅₀ = 6.6; n = −5.5 ± 0.16 (n = 3–6). K_Ca2.2 current was very small at −60 mV, only allowing meaned data to be fitted, yielding the following: pIC₅₀ = 5.6; n_h = −1.88 (n = 4). The shift in the onset of rectification was illustrated fitting normalized currents with Eq. 3 for (D) K_Ca2.2: pH 7.4, δ = 0.19, and ^MgK_d(0 mV) = 0.01 mM, and pH 5.5, δ = 0.16, and ^MgK_d(0 mV) = 0.01 mM, showing no effect on the affinity for the rectifying divalent ion by increasing [H⁺]_o and (E) K_Ca2.3: pH 7.4, δ = 0.22, and ^MgK_d(0 mV) = 0.09 mM, and pH 5.5, δ = 0.20, and ^MgK_d(0 mV) = 1.8 mM, showing a reduced affinity for intracellular divalent ions to evoke inward rectification at acidic extracellular pH. (F) The values of ^MgK_d(0 mV) from the fits of Eq. 3 over the full range of [H⁺]_o were plotted against pH and fitted with the Hill equation to give for pIC₅₀ = 6.14 and n_h = 4.2 for K_Ca2.3, whereas K_Ca2.2 showed no shift in ^MgK_d(0 mV).