title: Melatonin inhibits voltage-sensitive Ca(2+) 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 70mM K(+)-induced Ca(2+) increase at millimolar levels without effect on bradykinin-triggered Ca(2+) increase in PC12 cells. Melatonin (1mM) 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 70mM K(+)-induced norepinephrine release at a similar effective concentration range in PC12 cells. We confirmed that melatonin (100µM) 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 Ca(2+) channels and suggest a possible mechanism for the antiepileptic effect of melatonin.
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-749, Republic of Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Choi
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-749, Republic of Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Kwon
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-749, Republic of Korea.
authors.forename: Eunice Sung
authors.initials: ES
authors.lastname: Durrance
authors.affiliation: Department of Physiology, Institute of Bioscience and Biotechnology, BK21 Plus Graduate Program, Kangwon National University College of Medicine, Chuncheon 200-701, Republic of Korea.
authors.forename: Su-Hyun
authors.initials: SH
authors.lastname: Jo
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-749, Republic of Korea; Department of Life Sciences, Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea. Electronic address: sychoi@snu.ac.kr.
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Life Sciences, Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea. Electronic address: ktk@postech.ac.kr.
authors.forename: Kyong-Tai
authors.initials: KT
authors.lastname: Kim
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008550:Melatonin / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D044094:Receptors, Melatonin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D043705:Receptor, Adenosine A2A; D044094:Receptors, Melatonin; D000242:Cyclic AMP; D008550:Melatonin; D002118:Calcium; D009638:Norepinephrine
keywords: Epilepsy; Excitatory synaptic transmission; Melatonin; Neurotransmitter release; Receptor-independent manner; Voltage-sensitive Ca(2+) channel