Dual actions of lanthanides on ACTH-inhibited leak K(+) channels.
Bovine adrenal zona fasciculata cells express background K(+) channels (I(AC) channels) whose activity is potently inhibited by ACTH. In whole cell patch clamp recordings, it was discovered that the trivalent lanthanides (Ln(3+)s) lanthanum and ytterbium interact with two binding sites to modulate K(+) flow through these channels. Despite large differences in ionic radii, these Ln(3+)s inhibited I(AC) channels half-maximally with IC(50) values near 50 microM. In addition, these Ln(3+)s blocked and reversed ACTH-mediated inhibition of I(AC) K(+) channels at similar concentrations. The Ln(3+)s did not alter inhibition of I(AC) by angiotensin II or cAMP. Ln(3+)-induced uncoupling of ACTH receptor activation from I(AC) inhibition was prevented by raising the external Ca(2+) concentration from 2 to 10 mM. The divalent cation Ni(2+) (500 microM) also blocked ACTH-dependent inhibition of I(AC) through a Ca(2+)-sensitive mechanism. The results are consistent with a model in which Ln(3+)s produce opposing actions on I(AC) K(+) currents through two separate binding sites. In addition to directly inhibiting I(AC), Ln(3+)s (and Ni(2+)) bind with high affinity to a Ca(2+)-selective site associated with the ACTH receptor. By displacing Ca(2+) from this site, Ln(3+)s prevent ACTH from binding and accelerate its dissociation. These results identify Ln(3+)s as a relatively potent group of noncompetitive ACTH receptor antagonists. Allosteric actions of trivalent and divalent metal cations on hormone binding, mediated through Ca(2+)-specific sites, may be common to a variety of peptide hormone receptors.
Enyeart
John J
JJ
Department of Neuroscience, The Ohio State University, College of Medicine, Columbus, Ohio 43210.
Xu
Lin
L
Enyeart
Judith A
JA
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D000242:Cyclic AMP / Q000494:pharmacology; D004347:Drug Interactions; D004553:Electric Conductivity; D007700:Kinetics; D028581:Lanthanoid Series Elements / Q000494:pharmacology*; D007811:Lanthanum / Q000494:pharmacology; D008297:Male; D009532:Nickel / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects*; D018043:Receptors, Corticotropin / Q000378:metabolism; D015018:Ytterbium / Q000494:pharmacology; D015383:Zona Fasciculata / Q000378:metabolism*
D028581:Lanthanoid Series Elements; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D018043:Receptors, Corticotropin; D000804:Angiotensin II; D007811:Lanthanum; D009532:Nickel; D000255:Adenosine Triphosphate; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D015018:Ytterbium; D002118:Calcium