Model Depicting a Role of RanBP2 and Some of Its Partners in Metabolic and Neuronal Function
RanBP2 interacts with Cox11 and HKI and the triad is in equilibrium under normal physiological conditions. RanBP2 prevents the inhibition of HKI by Cox11 and its degradation. The ultimate effect of RanBP2 on its partners is the stimulation of the glycolytic pathway and production of ATP. The glycolytic pathway is critical to fuel the constitutive Na+/K+-ATPase pump to maintain the dark current between the inner and outer segment compartments of photosensory neurons. A deficit (haploinsufficiency) in RanBP2 disturbs the equilibrium between RanBP2, HKI, and Cox11. This pathophysiological event promotes the destabilization and degradation of HKI and a decrease in ATP production required to maintain the depolarization state neurons, and, hence, a reduction in the response of receptoral and postreceptoral neurons. A reduction in ATP levels also negatively modulates HKI activity/level. Decreased levels of HKI promote intracellular hyperglycemia and activate stress kinases, which modulate negatively the Na+/K+-ATPase pump by phosphorylation. Pathophysiological pathways promoted by RanBP2 haploinsufficiency are represented by dash lines. RIS, rod inner segment; ROS, rod outer segment.