Other proteins may also be regulated in this way in the ��-cell. For example, SUMO protein was shown to inhibit the voltage-dependent K+ channel Kv2.1 that resulted in widening of ��-cell action potentials and a decreased firing frequency, selleck chemical but inhibition of Kv2.1 might augment insulin secretion in mouse ��-cells (5, 14). Similarly, SUMO-mediated upregulation of signaling pathways in cellular stress, such as the NF-��B transcription pathway, might be beneficial under certain circumstances (7). On the other hand, a recent report shows that SUMO-1 impairs glucose-stimulated insulin secretion by binding to synaptogamin VII and preventing exocytosis (6). We found that overexpression of SUMO-1 resulted in intracellular retention of the GLP-1R that was associated with reduced receptor density at the cell membrane.

Even though the role of SUMO in nucleocytoplasmic trafficking is well documented (11), how SUMO aids in forward trafficking to the plasma membrane is yet to be investigated. One possibility is that SUMO prevents GLP-1R oligomerization. Receptor oligomerization is essential for forward trafficking of the secretin family of class B G protein-coupled receptors, of which the GLP-1R is a member (20). SUMO modification was also shown to inhibit oligomerization of other proteins such as apoptosis signal-regulating kinase 1 and E26 leukemia (TEL) protein (18, 38). Furthermore, enhanced SUMO modification increases solubility of proteins as in the case of vaccinea virus protein (26). Thus SUMO modification may affect GLP-1R oligomerization, perhaps by a change in the solubility or binding ability of sumoylated proteins.

The mechanism by which SUMO affects trafficking of GLP-1R could also be due to posttranslational modification of GLP-1R and concomitant effects on components of the trafficking machinery. Moreover, downregulation of GLP-1R signaling is likely due to a compound effect of direct SUMO modification of the GLP-1R and the possible modifications of the components of this pathway. For example, SUMO-mediated regulation of cAMP-specific phosphodiesterase-4D5 has been reported previously (19). Similarly, SUMO modification of transcription factors involved in insulin gene expression could also contribute to attenuation of exendin-4-stimulated insulin secretion (24, 32). Incretin responses and its use in therapy are becoming central to the treatment of type 2 diabetes.

Here, we describe sumoylation as a mechanism that regulates incretin responsiveness that could contribute to the reduction of the incretin effect in diabetes. A thorough understanding of the role of SUMO in incretin receptor regulation will help improve the efficacy of incretin-based therapy for diabetes. GRANTS This work was partially supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-48494 Entinostat and DK-063493, DK-075706, P60 DK-020595, the Blum-Kovler Foundation, and the Merck IIS Grant 38186.