Transient receptor potential canonical (TRPC) channels are non-selective calcium-permeable cation channels. It is suggested that TRPC4β is regulated by phospholipase C (PLC) signaling and is especially maintained by phosphatidylinositol 4,5-bisphosphate (PIP2 ). In this study, we present the regulation mechanism of the TRPC4 channel with PIP2 hydrolysis which is mediated by a channel-bound PLCδ1 but not by the GqPCR signaling pathway. Our electrophysiological recordings demonstrate that the Ca2+ via an open TRPC4 channel activates PLCδ1 in the physiological range, and it causes the decrease of current amplitude. The existence of PLCδ1 accelerated PIP2 depletion when the channel was activated by an agonist. Interestingly, PLCδ1 mutants which have lost the ability to regulate PIP2 level failed to reduce the TRPC4 current amplitude. Our results demonstrate that TRPC4 self-regulates its activity by allowing Ca2+ ions into the cell and promoting the PIP2 hydrolyzing activity of PLCδ1.

PURPOSE: This study aimed to assess the discomfort and factors influencing the discomfort of cancer patients with peripherally inserted central catheters (PICC). METHODS: A cross-sectional survey was conducted at a tertiary university-based hospital in Seoul in 2013. Subjects were eligible if patients were diagnosed with cancer and four weeks had passed since the PICC was inserted. Anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS) and discomfort was assessed with 8 questions developed through qualitative interviews and a literature review. Questions were about pain, interruption of daily activity or leisure, satisfaction, usefulness and feelings towards the PICC. RESULTS: Total 111 patients participated in the study. Over 75% of patients reported annoyance with PICC line. There was low positive correlation between discomfort due to PICC and anxiety. In anxious patients, patients discomfort was significantly higher than that of non-anxious patients. Significant factors influencing discomfort were gender, age, education level, PICC complications and anxiety. CONCLUSION: Patient engagement in selecting the type of catheter and individualized care considering the level of anxiety and patient demographics might help to reduce discomfort in cancer patients.
Anxiety ; Catheters* ; Cross-Sectional Studies ; Demography ; Depression ; Education ; Humans ; Leisure Activities ; Patient Participation ; Seoul ; Vascular Access Devices

PURPOSE: This study was planned to determine the efficacy and safety of mycophenolate mofetil (MMF) as a rescue treatment in patients with membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS) who were not responsive to standard therapy with steroid and immunosuppressive regimen. METHODS: We planned a prospective, non-randomized study from Oct. 2002 to Aug. 2009, including biopsy-proven MN or FSGS patients in Keimyung university Dongsan hospital. MMF was initiated at 0.5-0.75 g twice daily, and advanced as appropriate or as tolerated to 0.75-1 g twice daily. RESULTS: 14 cases with MN and 5 cases with FSGS was enrolled. The mean age of patients was 51.7+/-12.3 years, and mean treatment duration was 14.4+/-6.5 months. Five patients (26.4%) went into complete remission and the seven (36.8%) into partial remission. The mean value of 24hr total urine protein over the follow-up 6 months' period declined significantly from 7.6+/-6.2 g in pre-treatment, to 4.1+/-3.2 g in 3 months, and 3.1+/-2.1 g in 6 months (p=0.011). The mean 24hr total urine protein decreased from 7.5+/-6.3 g in pre-MMF to 1.9+/-1.8 g in post-MMF (p=0.001). The mean serum albumin rose from 3.2+/-0.8 g/dL in pre-MMF to 3.9+/-0.5 g/dL in post-MMF (p=0.001). There were no significant changes in mean value for WBC, hemoglobin, serum creatinine, and total cholesterol. Side effects of MMF were infrequent and generally mild. CONCLUSION: MMF appears effective in 63% of patients with MN and FSGS who are resistant to other forms of treatment. Studies with more cases and multicenter controlled trials are required to establish the role and standards of MMF in these disorders.
Cholesterol ; Creatinine ; Follow-Up Studies ; Glomerulonephritis, Membranous ; Glomerulosclerosis, Focal Segmental ; Hemoglobins ; Humans ; Mycophenolic Acid ; Prospective Studies ; Serum Albumin

Polycystic kidney disease 2-like-1 (PKD2L1), polycystin-L or transient receptor potential polycystin 3 (TRPP3) is a TRP superfamily member. It is a calcium-permeable non-selective cation channel that regulates intracellular calcium concentration and thereby calcium signaling. Although the calmodulin (CaM) inhibitor, calmidazolium, is an activator of the PKD2L1 channel, the activating mechanism remains unclear. The purpose of this study is to clarify whether CaM takes part in the regulation of the PKD2L1 channel, and if so, how. With patch clamp techniques, we observed the current amplitudes of PKD2L1 significantly reduced when coexpressed with CaM and CaMΔN. This result suggests that the N-lobe of CaM carries a more crucial role in regulating PKD2L1 and guides us into our next question on the different functions of two lobes of CaM. We also identified the predicted CaM binding site, and generated deletion and truncation mutants. The mutants showed significant reduction in currents losing PKD2L1 current-voltage curve, suggesting that the C-terminal region from 590 to 600 is crucial for maintaining the functionality of the PKD2L1 channel. With PKD2L1608Stop mutant showing increased current amplitudes, we further examined the functional importance of EF-hand domain. Along with co-expression of CaM, ΔEF-hand mutant also showed significant changes in current amplitudes and potentiation time. Our findings suggest that there is a constitutive inhibition of EF-hand and binding of CaM C-lobe on the channel in low calcium concentration. At higher calcium concentration, calcium ions occupy the N-lobe as well as the EF-hand domain, allowing the two to compete to bind to the channel.
Binding Sites ; Calcium ; Calcium Signaling ; Calmodulin ; Ion Channels ; Ions ; Patch-Clamp Techniques ; Polycystic Kidney Diseases ; Transient Receptor Potential Channels

Gα(q)-coupled receptor stimulation was implied in the activation process of transient receptor potential canonical (TRPC)1/4 and TRPC1/5 heterotetrameric channels. The inactivation occurs due to phosphatidylinositol 4,5-biphosphate (PI(4,5)P₂) depletion. When PI(4,5)P₂ depletion was induced by muscarinic stimulation or inositol polyphosphate 5-phosphatase (Inp54p), however, the inactivation by muscarinic stimulation was greater compared to that by Inp54p. The aim of this study was to investigate the complete inactivation mechanism of the heteromeric channels upon Gα(q)-phospholipase C β (Gα(q)-PLCβ) activation. We evaluated the activity of heteromeric channels with electrophysiological recording in HEK293 cells expressing TRPC channels. TRPC1/4 and TRPC1/5 heteromers undergo further inhibition in PLCβ activation and calcium/protein kinase C (PKC) signaling. Nevertheless, the key factors differ. For TRPC1/4, the inactivation process was facilitated by Ca²⁺ release from the endoplasmic reticulum, and for TRPC1/5, activation of PKC was concerned mostly. We conclude that the subsequent increase in cytoplasmic Ca²⁺ due to Ca²⁺ release from the endoplasmic reticulum and activation of PKC resulted in a second phase of channel inhibition following PI(4,5)P₂ depletion.
Calcium ; Cytoplasm ; Endoplasmic Reticulum ; GTP-Binding Proteins ; HEK293 Cells ; Inositol ; Phosphatidylinositol 4,5-Diphosphate ; Phospholipases ; Phosphotransferases ; Protein Kinase C ; Transient Receptor Potential Channels ; Type C Phospholipases