2-iodomelatonin prevents apoptosis of cerebellar granule neurons via inhibition of A-type transient outward K+ currents.
Compelling evidence indicates that excessive K+ efflux and intracellular K+ depletion are key early steps in apoptosis. Previously, we reported that apoptosis of cerebellar granular neurons induced by incubation under low K+ (5 mM) conditions was associated with an increase in delayed rectifier outward K+ current (IK) amplitude and caspase-3 activity. Moreover, the melatonin receptor antagonist 4P-PDOT abrogated the effects of 2-iodomelatonin on IK augmentation, caspase-3 activity and apoptosis. Here, we show that incubation under low K+/serum-free conditions for 6 hr led to a dramatic increase in the A-type transient outward K+ current (IA) (a 27% increase; n=31); in addition, fluorescence staining showed that under these conditions, cell viability decreased by 30% compared with the control. Treatment with 2-iodomelatonin inhibited the IA amplitude recorded from control and apoptotic cells in a concentration-dependent manner and modified the IA channel activation kinetics of cells under control conditions. Moreover, 2-iodomelatonin increased the viability of cell undergoing apoptosis. Interestingly, 4P-PDOT did not abrogate the effect of 2-iodomelatonin on IA augmentation under these conditions; in the presence of 4P-PDOT (100 microm), 2-iodomelatonin reduced the average IA by 41+/-4%, which was similar to the effect of 2-iodomelatonin alone. These results suggest that the neuroprotective effects of 2-idomelatonin are not only because of its antioxidant or receptor-activating properties, but rather that 2-iodomelatonin may inhibit IA channels by acting as a channel blocker.
Hu
Chang-Long
CL
Center for Brain Science Research, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai, China.
Liu
Zheng
Z
Gao
Zhen-Yu
ZY
Zhang
Zhi-Hong
ZH
Mei
Yan-Ai
YA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D003594:Cytoplasmic Granules / Q000187:drug effects*; D008550:Melatonin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
C044556:2-iodomelatonin; D008550:Melatonin