Melatonin inhibits voltage-sensitive Ca2+ channel-mediated neurotransmitter release

Abstract

Melatonin is involved in various neuronal functions such as circadian rhythmicity and thermoregulation. Melatonin has a wide range of pharmacologically effective concentration levels from the nanomolar to millimolar levels. Recently, the antiepileptic effect of high dose melatonin has been the focus of clinical studies; however, its detailed mechanism especially in relation to neurotransmitter release and synaptic transmission remains unclear. We studied the effect of melatonin at high concentrations on the neurotransmitter release by monitoring norepinephrine release in PC12 cells, and excitatory postsynaptic potential in rat hippocampal slices. Melatonin inhibits the 70 mM K+-induced Ca2+ increase at millimolar levels without effect on bradyldnin-triggered Ca2+ increase in PC12 cells. Melatonin (1 mM) did not affect A2A adenosine receptor-evoked cAMP production, and classical melatonin receptor antagonists did not reverse the melatonin-induced inhibitory effect, suggesting G-protein coupled receptor independency. Melatonin inhibits the 70 mM K+-induced norepinephrine release at a similar effective concentration range in PC12 cells. We confirmed that melatonin (100 mu M) inhibits excitatory synaptic transmission of the hippocampal Schaffer collateral pathway with the decrease in basal synaptic transmission and the increase in paired pulse ratio. These results show that melatonin inhibits neurotransmitter release through the blocking of voltage-sensitive Ca2+ channels and suggest a possible mechanism for the antiepileptic effect of melatonin. (c) 2014 Elsevier B.V. All rights reserved.