title: In vitro and in vivo effects of lead on specific 3H-PN200-110 binding to dihydropyridine receptors in the frontal cortex of the mouse brain.
abstract: It is assumed that several neurotoxic substances interfere with neuronal calcium channels. Therefore, we studied the effects of the heavy metals, cadmium, copper, lead, manganese, and zinc on the L-type calcium channels in the mouse brain. Characterization of the calcium channels was carried out using binding studies on homogenates from the frontal cortex with the DHP (dihydropyridine)-derivative, 3H-PN200-110, which binds with high affinity to the DHP-receptor inside the L-type calcium channel. Furthermore, the in vivo effects of lead on the DHP-receptors were investigated in perinatally exposed mice. In these animals, the analysis of saturation experiments with 3H-PN200-110 showed no changes in receptor density or ligand affinity due to the lead exposure. In vitro, 3H-PN200-110 binding is absolutely dependent on the presence of calcium. Divalent cations, such as magnesium or manganese, which normally block the physiological effects of calcium, also enhance DHP-receptor binding. Interestingly, ions such as lead, cadmium and copper stimulate 3H-PN200-110 binding at low concentrations (0.1-10 microM), but inhibit binding at higher concentrations. In contrast, zinc blocked DHP-receptor binding at low concentrations (< 100 microM) without any stimulating effects. These results suggest that modulation of the L-type calcium channel by heavy metal cations is one possible mechanism by which the regulation of calcium homeostasis in neurons is altered.
authors.affiliation: Institute für Pharmakologie und Toxikologie, Fakultät für Klinische Medizin, Mannheim, Universität Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schulte
authors.forename: W E
authors.initials: WE
authors.lastname: Müller
authors.forename: K D
authors.initials: KD
authors.lastname: Friedberg
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D020746:Calcium Channels, L-Type; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D017275:Isradipine / Q000378:metabolism*; D007854:Lead / Q000633:toxicity*; D008274:Magnesium / Q000494:pharmacology; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D009124:Muscle Proteins; D007854:Lead; D008274:Magnesium; D002118:Calcium; D017275:Isradipine