TRPV Cation Channels Are Essential For Glucose Sensing By AMPK

AMPK is a pivotal sensor for monitoring cellular metabolism,previous reports demonstrate that glucose deprivation triggers AMPK active through the lysosomal pathway,thereby activating or inhibiting the many downstream pathways to enhance the catabolism of the organism.Under glucose starvation,the AMP/ATP ratios are not elevated,and the level of fructose-1,6-biphosphate,the intermediate of the glycolysis,is significantly decreased,which cause the formation change of the FBP aldolase to initiate the assembly of AXIN-AMPK-LKB1 complex,thus enhance the activity of AMPK phosphorylate by LKB1.Although the precise mechanism of AMPK activity regulated by the aldolase is still unclear.In our study,through mass spectrometry analysis,we find that aldolase interacts with and inhibits transient receptor potential cation(TRPV)channels,resulting in a reduction of local calcium concentrations,which occurs at the contact sites between the endoplasmic reticulum(ER)and lysosomes by immunofluorescence confocal microscopy,structured-illumination microscopy(SIM)and stochastic optical reconstruction microscopy(STORM)techniques.This increases the interaction of TRPV and v-ATPase and decreases the association of the v-ATPase with aldolase to suppress its activity,then activating AMPK.Consistent with this,TRPV antagonists mimic the effects of glucose starvation on AMPK,while agonists reverse inhibition of v-ATPase by glucose starvation.Increased activity of v-ATPase by adding TRPV channels and calcium can be reconstituted in vitro by detecting the ability of ATP hydrolysis and acidification.In addition,the TRPV channels are both functionally and physically required for AMPK activation.Genetic depletion of TRPV by CRISPR blocks AMPK activation upon glucose starvation.Our study has defined the signaling route linking glucose/FBP-sensing by aldolase to the TRPV channels and to the v-ATPase,which in turn allows formation of the AXIN-based activation complex,leading to the activation of AMPK in low glucose.