Modulation of I(A) potassium current in adrenal cortical cells by a series of ten lanthanide elements

The modulation of I(A) K⁺ current by ten trivalent lanthanide (Ln³⁺) cations spanning the series with ionic radii ranging from 0.99 Å to 1.14 Å was characterized by the whale-cell patch clamp technique in bovine adrenal zona fasciculata (AZF) cells. Each of the ten Ln³⁺s reduced I(A) amplitude measured at +20 mV in a concentration-dependent manner. Smaller Ln³⁺s were the most potent and half-maximally effective concentrations (EC₅₀) varied inversely with ionic radius for the larger elements, Estimation of EC₅₀s yielded the following potency sequence: LU³⁺ (EC₅₀ = 3.0 μM) ~ Yb³⁺ (EC₅₀ = 2.7 μM) > Er³⁺(EC₅₀ = 3.7 μM) ≤ Dy³⁺ (EC₅₀ = 4.7 μM) > Gd³⁺ (EC₅₀ = 6.7 μM) ~ Sm³⁺ (EC₅₀ = 6.9 μM)> Nd³⁺ (EC₅₀ = 11.2 μM) > Pr³⁺ (EC₄₀ = 22.3 μM) > Ce³⁺ (EC₅₀ = 28.0 μM) > La³⁺ (EC₅₀ = 33.7 μM). Ln³⁺s altered selected voltage-dependent gating and kinetic parameters of I(A) with a potency and order of effectiveness that paralleled the reduction of I(A) amplitude. Ln³⁺s markedly slowed activation kinetics and shifted the voltage-dependence of I(A) gating such that activation and steady-state inactivation occurred at more depolarized potentials. In contrast, Ln³⁺s did not measurably alter inactivation or deactivation kinetics and only slightly slowed kinetics of inactivated channels returning to the closed state. Replacement of external Ca²⁺ with Mg²⁺ had no effect on the concentration-dependent inhibition of I(A) by Ln³⁺s. In contrast to their action on I(A) K⁺ current, Ln³⁺s inhibited T-type Ca²⁺ currents in AZF cells without slowing activation kinetics. These results indicate that Ln³⁺ modulate I(A) K⁺ channels through binding to a site on I(A) channels located within the electric field but which is not specific for Ca²⁺. They are consistent with a model where Ln³⁺ binding to negative charges on the gating apparatus alters the voltage-dependence and kinetics of channel opening. Ln³⁺s modulate transient K⁺ and Ca²⁺ currents by two fundamentally differnt mechanisms.