TRPC6:an underlying target for human glaucoma

Glaucoma is one of the leading causes of visual impairment and blindness worldwide. Of known risk factors for glaucoma, an increased in intraocular pressure is most highly correlated with glaucomatous damage. Irrespective of the cause, apoptosis of the retinal ganglion cells is the eventual outcome. It is widely accepted that glaucoma is a neurodegenerative disease that is strongly correlated with central nervous system disorders, such as Alzheimer's disease. These two disorders also share some similarities in pathogenic mechanisms. Recent studies suggest that the transient receptor potential canonical 6 channel could work together with brain-derived neurotrophic factor to promote neuron survival in brain and retina. In this study, we propose that transient receptor potential canonical 6 may contribute to the pathogenesis of human glaucoma and become a potential therapeutic target.

Effects of SKF-96365, a TRPC inhibitor, on melittin-induced inward current and intracellular Ca^2+ rise in primary sensory cells

Objective Melittin （MEL） is a major component of bee venom and can produce both persistent spontaneous nociception and pain hypersensitivity when injected subcutaneously in the periphery. The present study aimed to examine the roles of transient receptor potential canonical （TRPC） channels in mediation of MEL-indueed activation of primary nociceptive cells. Methods Whole-cell patch-clamp and laser scanning confocal calcium detection were used to evalu- ate the effects of SKF-96365, a TRPC inhibitor, applied on the acutely isolated dorsal root ganglion （DRG） cells of rat, on MEL-induced increase in intracellular calcium concentration （[Ca2＋]i） and inward current. Results Under voltage- clamp mode, 43.9% （40/91） DRG cells were evoked to give rise to the inward current by 2 pmol/L MEL, which could be significantly suppressed by 3 doses of SKF-96365 （1, 5 and 10μmol/L） in a dose-dependent manner. Of the other 210 cells, 67.6% responded to MEL with an intracellular Ca2＋ rise, as revealed by confocal calcium imaging. Of these MEL- sensitive cells, 46.5% （66/142） were suppressed by the highest dose of SKF-96365. Conclusion MEL-induced activation of small to medium-sized DRG cells can be suppressed by SKF-96365, suggesting the involvement of TRPC channels in the mediation of MEL-induced activation of primary nociceptive cells.

TRPC5 is essential in endothelium-dependent contraction of aorta from diet-induced obese mice

The role of the Ca^(2+)-permeable ion channel TRPC5 in regulating vasocontraction in obesity is poorly understood.Here,we investigated whether TRPC5 contributes to vascular dysfunction in obesity by promoting endothelium-dependent contraction via activation of cytosolic phospholipase A2(cPLA_(2))in the aortic endothelial cells of obese mice.Acetylcholine-induced endothelium-dependent relaxation and contraction in the aorta were measured us-ing wire myography.PLA_(2)activity was measured by the fluorogenic PLA_(2)substrate Bis-BODIPY^(TM)FL C_(11)-PC.The intracellular Ca^(2+)level in response to acetylcholine was measured by Fluo-4 fluorescence.Endothelium-derived contracting factors were assessed by enzyme immunoassay.Diet-induced obesity(DIO)attenuated endothelium-dependent vasodilation,enhanced endothelium-dependent contraction(EDC),and increased the expression of TRPC5 in the mouse aorta.Activation of TRPC5 promoted EDC in the wild-type mouse aorta,whereas pharma-cological inhibition and genetic knockout of TRPC5 decreased EDC in the DIO mouse aorta.Moreover,cPLA_(2)phosphorylation and activity were higher in aortic endothelial cells from DIO mice,and this was attenuated by inhibition and knockout of TRPC5.Cyclooxygenase 2(COX-2)expression was increased in DIO mouse endothe-lium and was decreased by a TRPC5 inhibitor and knockout of TRPC5.Release of prostaglandins F_(2α(PGF_(2α)and E 2(PGE 2)was involved in TRPC5-regulated EDC in DIO mice.This study demonstrated that TRPC5 contributes to endothelial and vascular dysfunction and is involved in EDC through activation of cPLA_(2)and enhanced COX-2-PGF_(2α)/PGE_(2)levels in DIO mice.