Glucocorticoid actions on synaptic plasma membranes: modulation of dihydropyridine-sensitive calcium channels.
We have previously shown that glucocorticoids accelerate depolarization-induced 45Ca2+ influx in synaptosomes isolated from rat cerebral cortex, indicating that the steroids may modulate voltage-dependent Ca2+ channels. The present study was undertaken to characterize the biochemical action of glucocorticoids on dihydropyridine-sensitive voltage-dependent Ca2+ channels known to be present in brain synaptosomes. The [3H]dihydropyridine labeled site was used as a marker to determine the levels of functional Ca2+ channels. No effect on equilibrium binding of [3H]PN 200-110 was found when membranes from disrupted synaptosomes were incubated with corticosterone as high as 1 microM. However, when intact synaptosomes were first incubated with corticosterone at 37 degrees C and then disrupted, a significant increase in [3H]PN 200-110 binding was found. Steroid incubation of synaptosomes at 0 degree C was ineffective. It appears that metabolic processes requiring intracellular factors were involved in the steroid action. In examining this possibility, [3H]PN 200-110 binding was activated in disrupted membranes by MgATP and Ca(2+)-calmodulin, and corticosterone was found to enhance the activation in a concentration-dependent manner. [3H]PN 200-110 binding to membranes was also activated by incubation with MgATP and cAMP-dependent protein kinase, but this activation was not enhanced by the steroid. These findings are consistent with the interpretation that the steroid promotes Ca2+ channel activity by enhancing calmodulin-dependent activation of the channels. The action on voltage-dependent Ca2+ channels in synaptic terminals may well be a mechanism whereby glucocorticoids modulate neuronal activity.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D020746:Calcium Channels, L-Type; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000502:physiology*; D000242:Cyclic AMP / Q000494:pharmacology; D004095:Dihydropyridines / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D017275:Isradipine / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D005938:Glucocorticoids; D009419:Nerve Tissue Proteins; D013256:Steroids; C038806:1,4-dihydropyridine; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017275:Isradipine