The Role of TRPM7 in Oncogenesis.

This review summarizes the current understanding of the role of transient receptor potential melastatin-subfamily member 7 (TRPM7) channels in the pathophysiology of neoplastic diseases. The TRPM family represents the largest and most diverse group in the TRP superfamily. Its subtypes are expressed in virtually all human organs playing a central role in (patho)physiological events. The TRPM7 protein (along with TRPM2 and TRPM6) is unique in that it has kinase activity in addition to the channel function. Numerous studies demonstrate the role of TRPM7 chanzyme in tumorigenesis and in other tumor hallmarks such as proliferation, migration, invasion and metastasis. Here we provide an up-to-date overview about the possible role of TRMP7 in a broad range of malignancies such as tumors of the nervous system, head and neck cancers, malignant neoplasms of the upper gastrointestinal tract, colorectal carcinoma, lung cancer, neoplasms of the urinary system, breast cancer, malignant tumors of the female reproductive organs, prostate cancer and other neoplastic pathologies. Experimental data show that the increased expression and/or function of TRPM7 are observed in most malignant tumor types. Thus, TRPM7 chanzyme may be a promising target in tumor therapy.

Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes.

Despite its widespread therapeutical use there is little information on the cellular cardiac effects of the antidiabetic drug pioglitazone in larger mammals. In the present study, therefore, the concentration-dependent effects of pioglitazone on ion currents and action potential configuration were studied in isolated canine ventricular myocytes using standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques. Pioglitazone decreased the maximum velocity of depolarization and the amplitude of phase-1 repolarization at concentrations ≥3 µM. Action potentials were shortened by pioglitazone at concentrations ≥10 µM, which effect was accompanied with significant reduction of beat-to-beat variability of action potential duration. Several transmembrane ion currents, including the transient outward K(+) current (Ito), the L-type Ca(2+) current (ICa), the rapid and slow components of the delayed rectifier K(+) current (IKr and IKs, respectively), and the inward rectifier K(+) current (IK1) were inhibited by pioglitazone under conventional voltage clamp conditions. Ito was blocked significantly at concentrations ≥3 µM, ICa, IKr, IKs at concentrations ≥10 µM, while IK1 at concentrations ≥30 µM. Suppression of Ito, ICa, IKr, and IK1 has been confirmed also under action potential voltage clamp conditions. ATP-sensitive K(+) current, when activated by lemakalim, was effectively blocked by pioglitazone. Accordingly, action potentials were prolonged by 10 µM pioglitazone when the drug was applied in the presence of lemakalim. All these effects developed rapidly and were readily reversible upon washout. In conclusion, pioglitazone seems to be a harmless agent at usual therapeutic concentrations.

Electrophysiological characteristics of heart ventricular papillary muscles in diabetic histidine decarboxylase knockout and wild-type mice.

OBJECTIVE: The diabetes-induced action potential (AP) abnormalities have been studied mainly in rats where significant prolongation of repolarization and reduced maximum rate of depolarization (Vmax) was detected. Histidine decarboxylase knockout (HDC-KO) mice lack endogenous histamine and they are characterized by impaired glucose tolerance. Furthermore they have autoantibodies reactive to glutamic acid decarboxylase (GAD). These findings suggested that this model might have an increased susceptibility to autoimmune diabetes. MATERIALS AND METHODS: Standard microelectrode technique was used to characterise the cardiac electrophysiological parameters of control and Streptozotocin (STZ) induced diabetic HDC-KO mice comparing with those of wild type animals. RESULTS: With aging, blood glucose levels in HDC-KO mice were shifted towards values characteristic of diabetes. The electrophysiological changes relevant to diabetes i.e. prolongation of repolarization and depression of Vmax developed without any induction with STZ. In this group STZ treatment caused no further significant AP changes. CONCLUSIONS: One of the likely explanations may be that in the chain of events in HDC-KO mice on the one hand and in Streptozotocin-induced diabetes on the other hand, leading to the alterations in the heart electrophysiological parameters, there is a common link. This link may be a similar shift in the expression/function of certain K+ channel populations.

Immunoreactive endomorphin 2 is generated extracellularly in rat isolated L4,5 dorsal root ganglia by DPP-IV.

BACKGROUND AND AIMS: The gene(s) encoding for endomorphin precursor(s) is/are still unknown. We have raised the possibility of and did find some evidence for a potential de novo biosynthetic route starting from Tyr-Pro precursor. To pursue further this possibility we measured the generation of immunoreactive endomorphin-2 (E2-IR) in adult rat isolated L4,5 dorsal root ganglia. RESULTS AND CONCLUSIONS: In rat isolated dorsal root ganglia the combination of presumed biosynthetic precursor of endomorphin 2 (E2), Tyr-Pro with the dipeptidyl peptidase IV (DPP-IV) inhibitor Ile-Pro-Ile generated 1.60+/-0.37 pg/mg Wet Tissue Weight_30 min E2-IR in the bathing fluid (n=4) with an 8-fold increase upon depolarization whereas the tissue content was low (0.50+/-0.08 pg/mg_WTW). Substance P, as determined by ELISA in the pilot experiments, was found almost exclusively within the tissues. It is concluded that E2-IR was generated extracellularly by a membrane-bound DPP-IV, which was switched to "synthase" mode by the hydrolase inhibitor Ile-Pro-Ile. DPP-IV was depolarization-sensitive in "synthase" functional mode.