MODULATION OF I-A POTASSIUM CURRENT IN ADRENAL-CORTICAL CELLS BY A SERIES OF 10 LANTHANIDE ELEMENTS

The modulation of I-A K+ current by ten trivalent lanthanide (Ln(3+)) cations spanning the series with ionic radii ranging from 0.99 Angstro m to 1.14 Angstrom was characterized by the whole-cell patch clamp tec hnique in bovine adrenal zona fasciculata (AZF) cells. Each of the ten Ln(3+)s reduced I-A amplitude measured at +20 mV in a concentration-d ependent manner. Smaller Ln(3+)s were the most potent and half-maximal ly effective concentrations (EC(50)s) varied inversely with ionic radi us for the larger elements. Estimation of EC(50)s yielded the followin g potency sequence: Lu3+ (EC50 = 3.0 mu M) approximate to Yb3+ (EC50 = 2.7 mu M) > Er3+ (EC50 = 3.7 mu M) greater than or equal to Dy3+ (EC5 0 = 4.7 mu M) > Gd3+ (EC50 = 67 mu M) approximate to Sm3+ (EC50 = 6.9 mu M) > Nd3+ (EC50 = 11.2 mu M) > Pr3+ (EC50 = 22.3 mu M) > Ce3+ (EC50 = 28.0 mu M) > La3+ (EC50 = 33.7 mu M). Ln3+s altered selected voltag e-dependent gating and kinetic parameters of I-A with a potency and or der of effectiveness that paralleled the reduction of I-A amplitude. L n(3+)s markedly slowed activation kinetics and shifted the voltage-dep endence of I-A gating such that activation and steady-state inactivati on occurred at more depolarized potentials. In contrast, Ln(3+)s did n ot measurably alter inactivation or deactivation kinetics and only sli ghtly slowed kinetics of inactivated channels returning to the closed state. Replacement of external Ca2+ with Mg2+ had no effect on the con centration-dependent inhibition of I-A by Ln(3+)s. In contrast to thei r action on I-A K+ current, Ln(3+)s inhibited T-type Ca2+ currents in AZF cells without slowing activation kinetics. These results indicate that Ln(3+) modulate I-A K+ channels through binding to a site on I-A channels located within the electric field but which is not specific f or Ca2+. They are consistent with a model where Ln(3+) binding to nega tive charges on the gating apparatus alters the voltage-dependence and kinetics of channel opening. Ln(3+)s modulate transient K+ and Ca2+ c urrents by two fundamentally different mechanisms.