The Role Of Adrenergic Receptor Dependent Phosphorylation Of Inositol Hexaphosphate Kinase 1(IP6K1) In Glucagon Secretion

Adrenergic receptors(AR)are classical G-protein coupled receptors activated by sympathetic neurotransmitters such as adrenaline and nor-adrenaline,thereby initiating intracellular signal transduction pathways to produce important biological effects.Inositol hexaphosphate kinase 1(IP6K1)is a widely expressed enzyme that catalyzes the conversion of inositol hexaphosphate(IP6)to inositol pyrophosphate(IP7)in vivo.More and more in-depth studies have increasingly found that the inositol pyrophosphate IP7 has essential functions in biological activities,among which are its notable role in insulin secretion and insulin resistance,which attracts widespread attention to study IP6K1's potential as a drug target of diabetes treatment.In this thesis,we found that the adrenergic receptor stimulation increases IP6K1 phosphorylation.A detailed AR-Gs-AC-c AMP-PKA-IP6K1 signaling axis is validated as the signal transduction pathway leading to IP6K1 activation in HEK293 cells and mouse islet ? cell line Alpha TC1-6.In addition,we also characterized the function of IP6K1 phosphorylated by adrenergic receptor stimulation,demonstrating increased IP7 production upon raising the concentration of c AMP.These results suggest that the small metabolite IP7 could be a new type of second messenger synthesized in response to extracellular stimuli,and transduces such signals to downstream targets for functional output accordingly.As the downstream of the most classical signaling pathway,IP6K1 participates in life activities,and its importance is self-evident.We also search for the biological process that IP6K1 participates in after responding to sympathetic neurotransmitters.In C57BL/6 mice with a mutation mimicking phosphorylation(S118D/S121D)of IP6K1,higher level of serum glucagon after fasting(compared with the wild type mice)was detected,while the islets of IP6K1-KO mice showed significantly impaired glucagon secretion ability.These data are consistent with a role for IP6K1 in mediating sympathetic stimulation of glucagon secretion.Thus,as a newly identified downstream effector of the classical adrenergic GPCR pathway,IP6K1 plays an important role in the regulation of blood glucose homeostasis.Manipulating this function of IP6K1 have implications in the development and targeting of diabetes.