The ins and outs of vesicular monoamine transporters

The H+-coupled vesicular monoamine transporter (VMAT) is a transporter essential for life. VMAT mediates packaging of the monoamines serotonin, dopamine, norepinephrine, and histamine from the neuronal cytoplasm into presynaptic vesicles, which is a key step in the regulated release of neurotransmitters. However, a detailed understanding of the mechanism of VMAT function has been limited by the lack of availability of high-resolution structural data. In recent years, a series of studies guided by homology models has revealed significant insights into VMAT function, identifying residues that contribute to the binding site and to specific steps in the transport cycle. Moreover, to characterize the conformational transitions that occur upon binding of the substrate and coupling ion, we have taken advantage of the unique and powerful pharmacology of VMAT as well as of mutants that affect the conformational equilibrium of the protein and shift it toward defined conformations. This has allowed us to identify an important role for the proton gradient in driving a shift from lumen-facing to cytoplasm-facing conformations.

Functional Imaging of Paragangliomas with an Emphasis on Von Hippel–Lindau-Associated Disease: A Mini Review

Few reports have presented data and results on functional (i.e., nuclear medicine) imaging of paragangliomas and pheochromocytomas (PGLs/PHEOs) for von Hippel–Lindau (VHL) patients. Nuclear medicine localization modalities for chromaffin tumors can be specific or nonspecific. Specific methods make use of the expression of the human norepinephrine transporter (hNET) and vesicular monoamine transporters (VMATs) by these tumors. These permit the use of radiolabeled ligands that enter the synthesis and storage pathway of catecholamines. Nonspecific methods are not related to the synthesis, uptake, or storage of catecholamines but make use of the tumors’ high glucose metabolism or expression of somatostatin receptors. Consensuses and guidelines suggest that metastatic and sporadic PHEOs/PGLs in VHL patients (as in patients with chromaffin tumors of yet unknown genotype) should be evaluated first with 18F-dihydroxyphenylalanine (18F-DOPA) positron emission tomography/computed tomography (PET/CT). The functional imaging of second choice is 123I-metaiodobenzylguanidine (123I-MIBG) for PHEOs in VHL patients. 123I-MIBG, 68Ga-DOTATATE/DOTATOC/DOTANOC PET/CT, or 18F-fluorodeoxyglucose (18F-FDG) PET/CT can be a second choice of functional imaging for PGLs in VHL patients.

Syrosingopine sensitizes cancer cells to killing by metformin

We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine’s known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme α-enolase in vitro, and the expression of the γ-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. Thus, combining syrosingopine and codrugs is a promising therapeutic strategy for clinical application for the treatment of cancer.