Modulation of IA potassium current in adrenal cortical cells by a series of ten lanthanide elements.
The modulation of IA K+ current by ten trivalent lanthanide (Ln3+) cations spanning the series with ionic radii ranging from 0.99 A to 1.14 A was characterized by the whole-cell patch clamp technique in bovine adrenal zona fasciculata (AZF) cells. Each of the ten Ln3+s reduced IA amplitude measured at +20 mV in a concentration-dependent manner. Smaller Ln3+s were the most potent and half-maximally effective concentrations (EC50s) varied inversely with ionic radius for the larger elements. Estimation of EC50s yielded the following potency sequence: Lu3+ (EC50 = 3.0 microM) approximately Yb3+ (EC50 = 2.7 microM) > Er3+ (EC50 = 3.7 microM) >/= Dy3+ (EC50 = 4.7 microM) > Gd3+ (EC50 = 6.7 microM) approximately Sm3+ (EC50 = 6.9 microM) > Nd3+ (EC50 = 11.2 microM) > Pr3+ (EC50 = 22.3 microM) > Ce3+ (EC50 = 28.0 microM) > La3+ (EC50 = 33.7 microM). Ln3+s altered selected voltage-dependent gating and kinetic parameters of IA with a potency and order of effectiveness that paralleled the reduction of IA amplitude. Ln3+s markedly slowed activation kinetics and shifted the voltage-dependence of IA 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 IA by Ln3+s. In contrast to their action on IA K+ current, Ln3+s inhibited T-type Ca2+ currents in AZF cells without slowing activation kinetics. These results indicate that Ln3+ modulate IA K+ channels through binding to a site on IA 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 different mechanisms.
Enyeart
J J
JJ
Department of Pharmacology, The Ohio State University College of Medicine, 5188 Graves Hall, 333 W. 10th Ave., Columbus, OH 43210-1239, USA.
Xu
L
L
Gomora
J C
JC
Enyeart
J A
JA
D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008674:Metals, Rare Earth / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D013997:Time Factors
D008674:Metals, Rare Earth; D015221:Potassium Channels