Fig. 7: Model of ISX-9 effect through CaMKIIδ-mediated activation of BMAL1 for circadian amplitude enhancement.
From: ISX-9 potentiates CaMKIIδ-mediated BMAL1 activation to enhance circadian amplitude
Aging is commonly associated with the declined circadian amplitude of clock gene expressions, decreased locomotor activity, and reduced sleep homeostasis. ISX-9 facilitates Ca2+ influx further triggers BMAL1 S513/515/516 phosphorylation in a CaMKIIδ-dependent manner in aging cells. The effect, in turn, upregulates the expression clock outputs, including PER2, DBP, and REV-ERBα, and promotes locomotor activity, daily RER fluctuation, and sleep homeostasis in middle-aged mice. Given that CaMKIIδ is a clock-controlled protein that also dampens with aging, ISX-9 stimulation helps to intensify a positive feedback loop through CaMKIIδ to modulate BMAL1 activity, therefore, reverts the circadian amplitude decay caused by aging.
