GIRK Channels Mediate the Nonphotic Effects of Exogenous Melatonin

Abstract

Melatonin supplementation has been used as a therapeutic agent for several diseases, yet little is known about the underlying mechanisms by which melatonin synchronizes circadian rhythms. G-protein signaling plays a large role in melatonin-induced phase shifts of locomotor behavior and melatonin receptors activate G-protein-coupled inwardly rectifying potassium (GIRK) channels in Xenopus oocytes. The present study tested the hypothesis that melatonin influences circadian phase and electrical activity within the central clock in the suprachiasmatic nucleus (SCN) through GIRK channel activation. Unlike wild-type littermates, GIRK2 knock-out (KO) mice failed to phase advance wheel-running behavior in response to 3 d subcutaneous injections of melatonin in the late day. Moreover, in vitro phase resetting of the SCN circadian clock by melatonin was blocked by coadministration of a GIRK channel antagonist tertiapin-q (TPQ). Loose-patch electrophysiological recordings of SCN neurons revealed a significant reduction in the average action potential rate in response to melatonin. This effect was lost in SCN slices treated with TPQ and SCN slices from GIRK2 KO mice. The melatonin-induced suppression of firing rate corresponded with an increased inward current that was blocked by TPQ. Finally, application of ramelteon, a potent melatonin receptor agonist, significantly decreased firing rate and increased inward current within SCN neurons in a GIRKdependent manner. These results are the first to show that GIRK channels are necessary for the effects of melatonin and ramelteon within the SCN. This study suggests that GIRK channels may be an alternative therapeutic target for diseases with evidence of circadian disruption, including aberrant melatonin signaling.

Inhibition of ERK1/2 Signaling Pathway is Involved in Melatonin's Antiproliferative Effect on Human MG-63 Osteosarcoma Cells

“…Melatonin plays key roles in the biologic regulation of circadian rhythms [27,28], sleep [29,30], antioxidant protection [31][32][33][34][35], cell aging [36], tumor growth [12,37], reproduction [31,38], and bone physiology [39,40]. A growing amount of data indicates that the age-related decline in the level of melatonin is closely associated with bone diseases: osteosarcoma, adolescent idiopathic scoliosis and osteoporosis [1,39].…”

The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus

“…Moreover, potassium induced depolarization several hours after NPY application completely blocks the NPY-induced phase shifts, suggesting that the resting membrane potential is critically important for phase resetting (Besing et al, 2012). NPY and other neurotransmitters that typically produce phase advances during the day, hyperpolarize the resting membrane potential and reduce firing rate through activation of G-protein coupled inwardly rectifying K + (GIRK) channels (Scott et al, 2010; Hablitz et al, 2014, 2015). Together, these results suggest that sustained changes in membrane potential at specific phases of the circadian cycle are key to resetting the circadian pacemaker.…”

Melatonin receptor activation increases glutamatergic synaptic transmission in the rat medial lateral habenula

“…The most recognized signaling pathway associated with MT 1 and MT 2 receptors is through Gi/o inhibition of adenylyl cyclase resulting in decreased formation of cAMP (Drew et al, ), activation of inward rectifier potassium channels (GIRK) (Hablitz et al, ; van den Top et al, ) and inhibition of calcium currents (For review see, Dubocovich et al, ). Classically, activation of these signaling pathways decreases neuronal activity and inhibits neurotransmitter release (van den Top et al, ).…”