A chloride channel widely expressed in epithelial and non-epithelial cells

Chloride channels have several functions, including the regulation of cell volume, stabilizing membrane potential, signal transduction and transepithelial transport. The plasma membrane Cl- channels already cloned belong to different structural classes: ligand-gated channels, voltage-gated channels, and possibly transporters of the ATP-binding-cassette type (if the cystic fibrosis transmembrane regulator is a Cl- channel). The importance of chloride channels is illustrated by the phenotypes that can result from their malfunction: cystic fibrosis, in which transepithelial transport is impaired, and myotonia, in which ClC-1, the principal skeletal muscle Cl- channel, is defective. Here we report the properties of ClC-2, a new member of the voltage-gated Cl- channel family. Its sequence is approximately 50% identical to either the Torpedo electroplax Cl- channel, ClC-0 (ref. 8), or the rat muscle Cl- channel, ClC-1 (ref. 9). Isolated initially from rat heart and brain, it is also expressed in pancreas, lung and liver, for example, and in pure cell lines of fibroblastic, neuronal, and epithelial origin, including tissues and cells affected by cystic fibrosis. Expression in Xenopus oocytes induces Cl- currents that activate slowly upon hyperpolarization and display a linear instantaneous current-voltage relationship. The conductivity sequence is Cl- greater than or equal to Br- greater than I-. The presence of ClC-2 in such different cell types contrasts with the highly specialized expression of ClC-1 (ref. 9) and also with the cloned cation channels, and suggests that its function is important for most cells

Regions involved in the opening of CIC-2 chloride channel by voltage and cell volume

Regulation of cell volume is essential for every cell and is accomplished by the regulated loss or gain of intracellular ions or other osmolytes. Regulatory volume decrease often involves the parallel activation of potassium and chloride channels. Overexpression of P-glycoprotein leads to volume-activated Cl- currents but its physiological importance for volume regulation is unclear. CIC-2 is a ubiquitously expressed Cl- channel activatable by non-physiologically strong hyperpolarization. We now show that CIC-2 can be activated by extracellular hypotonicity, which suggests that it has a widespread role in volume regulation. Domains necessary for activation by both voltage and volume are localized to the amino terminus. Mutations in an 'essential' region lead to constitutively open channels unresponsive to medium tonicity, whereas deletions in a 'modulating' region produce partially opened channels responsive to both hypo- and hypertonicity. These domains can be transplanted to different regions of the protein without loss of function

Assessing Pain and Functional Outcomes of Percutaneous Stabilization of Metastatic Pelvic Lesions via Photodynamic Nails

Background:. Minimally invasive surgical interventions for metastatic invasion of the pelvis have become more prevalent and varied. Our group hypothesized that the use of percutaneous photodynamic nails (PDNs) would result in decreased pain, improved functional outcomes and level of ambulation, and decreased use of opioid pain medication. Methods:. We performed a retrospective chart review of patients with metastatic pelvic bone disease undergoing stabilization with PDNs (IlluminOss Medical) at 2 institutions. Functional outcome measures assessed include the Combined Pain and Ambulatory Function (CPAF), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function, and PROMIS Global Health-Physical. Pain was assessed using a visual analog scale (VAS). Outcomes were assessed preoperatively and at 6 weeks, 3 months, 6 months, and 1 year following surgery. Results:. A total of 39 patients treated with PDNs were included. No cases of surgical site infection or implant failure were identified. The median pain VAS score decreased from 8 preoperatively to 0 at the 6-week time point (p < 0.0001). The median CPAF score improved from 5.5 points preoperatively to 7 points at the 3-month mark (p = 0.0132). A significant improvement in physical function was seen at 6 months in the PROMIS Physical Function (p = 0.02) and at both 6 months (p = 0.01) and 1 year (p < 0.01) for the PROMIS Global Health-Physical. The rate of patients prescribed opioid analgesia dropped from 100% preoperatively to 20% at 6 months following surgery (p < 0.001). By 6 weeks, all patients were fully weight-bearing and able to walk independently with or without assistive devices. Conclusions:. Percutaneous stabilization of metastatic periacetabular defects using PDNs is a safe and effective palliative procedure that has been shown to improve patient mobility and provide early pain relief. Level of Evidence:. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence

Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers

<h4 id="absSec_2">Background</h4>\ud \ud There is evidence of abnormal cerebral dopamine transmission in nicotine-dependent smokers, but it is unclear whether dopaminergic abnormalities are due to acute nicotine abuse or whether they persist with abstinence. We addressed this question by conducting longitudinal positron emission tomography (PET) examination of smokers before and after 3 months of abstinence.</p><h4 id="absSec_2">Methods</h4><p id="sp0060">We obtained baseline 6-[¹⁸F]fluoro-L-DOPA (FDOPA)-PET scans in 15 nonsmokers and 30 nicotine-dependent smokers, who either smoked as per their usual habit or were in acute withdrawal. All smokers then underwent cessation treatment, and successful abstainers were re-examined by FDOPA-PET after 3 months of abstinence (<em>n</em> = 15). Uptake of FDOPA was analyzed using a steady-state model yielding estimates of the dopamine synthesis capacity (K); the turnover of tracer dopamine formed in living brain (k_loss); and the tracer distribution volume (V_d), which is an index of dopamine storage capacity.</p><h4 id="absSec_3">Results</h4><p id="sp0065">Compared with nonsmokers, K was 15% to 20% lower in the caudate nuclei of consuming smokers. Intraindividual comparisons of consumption and long-term abstinence revealed significant increases in K in the right dorsal and left ventral caudate nuclei. Relative to acute withdrawal, V_d significantly decreased in the right ventral and dorsal caudate after prolonged abstinence. Severity of nicotine dependence significantly correlated with dopamine synthesis capacity and dopamine turnover in the bilateral ventral putamen of consuming smokers.</p><h4 id="absSec_4">Conclusions</h4><p id="sp0070">The results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention and cessation treatments