Melatonin receptor agonist 2‐iodomelatonin prevents apoptosis of cerebellar granule neurons via K⁺ current inhibition

Abstract

Activation of K(+) current plays a critical role in the control of programmed cell death. In the present study, whole-cell patch-clamp recording, a caspase-3 activity assay, and flow cytometric analysis were used to examine the effects of the MT2 melatonin receptor agonist 2-iodomelatonin on the delayed-rectifier K(+) current (IK) and the prevention of apoptosis. It was found that apoptosis of cerebellar granular neurons induced by low-K(+) (5 mm) incubation was associated with an increase in IK amplitude and caspase-3 activity. After 6 hr of low-K(+) treatment, IK was increased by 45% (n = 86). Flow cytometry showed that the apoptosis rate increased by 333% compared with the control neurons. In addition, exposure of cultured granule cells to low K(+) also resulted in a significant activation of caspase-3, by 466%. 2-Iodomelatonin (10 microm in injection pipette) inhibited the IK amplitude recorded from control cells and from cells undergoing apoptosis. However, 2-iodomelatonin only modified the IK-channel activation kinetics of cells under both conditions. Furthermore, 2-iodomelatonin reduced the rate of apoptosis and caspase-3 activation, by 66 and 64%, respectively. The melatonin receptor antagonist, 4P-PDOT, abrogated the effect of 2-iodomelatonin on the IK augmentation, caspase-3 activity, and apoptosis. These results suggest that the neuroprotective effects of melatonin are not only because of its function as a powerful antioxidant, but also to its interactions with specific receptors. The effect of 2-iodomelatonin against apoptosis may be mediated by activating a melatonin receptor, which modulates IK channels and reduces K(+) efflux.

Hydrogen peroxide enhanced Ca2+-activated BK currents and promoted cell injury in human dermal fibroblasts

“…It is well known that K + channel-mediated signals play an important role in cell death or apoptosis (Jiao et al, 2004;Yu et al, 1997). We next examined whether the H 2 O 2 -induced increase in BK currents was associated with H 2 O 2 -induced cell injury.…”

“…Among the different types of voltage-dependent potassium channels (K V ), the I K channels are thought to play important roles in apoptosis due to their high K + conductance and their slow or non-inactivation behaviour (Jiao et al, 2004;Yu et al, 1997). The K Ca current, which is associated with apoptosis, has been reported in a wide variety of cells (Krick et al, 2002;Ma et al, 2010).…”

Differential Regulation of Cell Proliferation and Apoptosis by Melatonin Receptor Subtype-Signaling in the Adult Murine Brain

“…Therefore, we suggest that regulation of timing and quantity of apoptotic cells by melatonin requires both MT subtypes. Several studies already indicated that melatonin exerts effects on apoptosis via its receptors [70][71][72][73]. However, to our knowledge, the present study is the first to show that actually both, MT1 and MT2, are required for a specific functional role of melatonin within apoptosis under physiological conditions, namely the proper timing of diurnal changes in the number of apoptotic cells in the brain and pituitary.…”

Therapeutical Implications of Melatonin in Alzheimer’s and Parkinson’s Diseases

“…Bcl-2 is capable of blocking the apoptotic pathway in the mitochondria by preventing the formation of a functional mitochondrial permeability transition pore (mtPTP) and, thus, the release of the mitochondrial enzyme cytochrome c, which represents the fi nal and no-return signal of the apoptotic program (Khandelwal et al 2011 ). Studies in vitro indicate that melatonin enhances expression of Bcl-2 and prevents apoptosis (Jiao et al 2004 ;Koh 2011 ;Radogna et al 2010 ). In addition, melatonin directly inhibits the opening of the mtPTP, thereby rescuing cells (Peng et al 2012 ;Jou 2011 ;Andrabi et al 2004 ).…”