Journal
MOLECULAR PHARMACOLOGY
Volume 62, Issue 6, Pages 1418-1430Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.62.6.1418
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- NIEHS NIH HHS [ES05822] Funding Source: Medline
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Lead (Pb2+) is a well-known inhibitor of voltage-dependent Ca2+ channels in their native environments in several types of cells. However, its effects on discrete Ca2+ channel phenotypes in isolation have not been well studied. We compared how specific subtypes of human neuronal high-voltage-activated Ca2+ channels were affected by acute exposure to Pb2+. Expression cDNA clones of human alpha(1C), alpha(1B), or alpha(1E) subunit genes encoding neuronal L-, N-, and R-subtypes of Ca2+ channels, respectively, along with a constant alpha(2)delta and beta(3) subunits were transfected into human embryonic kidney 293 cells. Currents through the respective transiently expressed channels were measured using whole-cell recording techniques with Ba2+ (20 mM) as charge carrier. Extracellular bath applications of Pb2+ significantly reduced current amplitude through all three types of Ca2+ channels in a concentration-dependent manner. The order of potency was: alpha(1E) (IC50 = 0.10 muM), followed by alpha(1C) (IC50 = 0.38 muM) and alpha(1B) (IC50 = 1.31 muM). Pb2+-induced perturbation of function of alpha(1C) and alpha(1B) containing Ca2+ channels was more easily reversed than for alpha(1E)-containing Ca2+ channels after washing with Pb2+ free solution. The current-voltage relationships were not altered after 3-min exposure to Pb2+ for any of the three types. However, the steady-state inactivation relationships were shifted to more negative potentials for channels containing alpha(1B) and alpha(1E) subunits, but not for those containing alpha(1C) subunits. Pb2+ accelerated the inactivation time of current in all three subtypes of Ca2+ channels in a concentration- and voltage-dependent manner. Therefore, different subtypes of Ca2+ channels exhibit differential susceptibility to Pb2+ even when expressed in the same cell type. Current expressed by alpha(1E)-containing channels is more sensitive to Pb2+ than that expressed by alpha(1C)- or alpha(1B)-containing channels. Several Ca2+ channel phenotypes are quite sensitive to the inhibitory action of Pb2+. Furthermore, it seems that Pb2+ is more likely to combine with Ca2+ channels in the closed state.
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