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.
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.
Schulte
S
S
Institute für Pharmakologie und Toxikologie, Fakultät für Klinische Medizin, Mannheim, Universität Heidelberg, Germany.
Müller
W E
WE
Friedberg
K D
KD
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*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D009124:Muscle Proteins; D007854:Lead; D008274:Magnesium; D002118:Calcium; D017275:Isradipine