Transient receptor potential melastatin 7 (TRPM7) channels are novel Ca 2؉ -permeable non-selective cation channels ubiquitously expressed. Activation of TRPM7 channels has been shown to be involved in cellular Mg 2؉ homeostasis, diseases caused by abnormal magnesium absorption, and in Ca 2؉ -mediated neuronal injury under ischemic conditions. Here we show strong evidence suggesting that TRPM7 channels also play an important role in cellular Zn 2؉ ] i measurement have been questionable. For example, previous studies reported that some indicators commonly used for calcium imaging, e.g. Calcium Green-1 and fura-2, are responsive to zinc with an extremely high affinity, and that specific zinc chelators reduced the intensity of calcium indicators (4 -7). These findings suggest that some of the biological effects previously assumed to be mediated by Ca 2ϩ may be mediated, at least partially, by zinc ions. Like calcium, recent studies have demonstrated that zinc ions play an important role in neuronal injuries associated with various neurological conditions (8, 9). The exact pathways mediating intracellular zinc accumulations and toxicity are, however, not clear.Zinc is one of the most crucial trace metals in cells. For example, zinc is required for the function of a broad range of enzymes involved in transcription, protein synthesis, and signal transductions (10). Although there are low levels of free zinc in cells, most zinc ions are bound to intracellular proteins (11). The mechanisms that affect the free zinc concentration are, therefore, pivotal for maintaining normal brain function. Although the extracellular fluid may contain up to several micromolar of zinc, intracellular zinc concentration ([Zn 2ϩ ] i ) is generally maintained at 10 Ϫ9 -10 Ϫ10 M (10, 12, 13). This steep gradient across the cell membrane is maintained primarily by zinc extrusion systems such as zinc transporters (ZnTs). At least 10 members of ZnTs, with different tissue distribution, have been identified in the ZnTs family. They promote the efflux of intracellular zinc into extracellular space or uptake of zinc into vesicles (14,15). In contrast to ZnTs, Zrt-and Irt-like proteins, or ZIPs, are known to transport zinc into the cells (14, 15). In addition, some calcium channels, e.g. voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate (NMDA) receptors, and amino-3-hydroxy-5-methyl-4-isoxazol propionate (AMPA)/kinate receptors have been reported to be zinc permeable (16,17). The activities of these channels thus affect intracellular zinc homeostasis and toxicity. Unfortunately, clinical trials using the antagonists of these channels failed to provide satisfactory neuroprotection (2, 3).Transient receptor potential melastatin 7 (TRPM7) is a member of the large TRP channel superfamily expressed in * This work was supported, in whole or in part, by National Institutes of Health Grants R01NS47506 and R01NS49470 and American Heart Association Grant 0840132N.

The addition of glucagon delivery to a closed-loop system with automated exercise detection reduces hypoglycemia in physically active adults with type 1 diabetes.

Aims Exercise increases risk of hypoglycemia in type 1 diabetes (T1D). An artificial pancreas (AP) can help mitigate this risk. We tested whether adjusting insulin and glucagon in response to exercise within a dual-hormone AP reduces exercise-related hypoglycemia. Materials and Methods In random order, 21 adults with T1D underwent three 22 h sessions: AP with exercise dosing adjustment (APX), AP with no exercise dosing adjustment (APN), and sensor-augmented pump therapy (SAP). After an overnight stay and 2 hours after breakfast, participants exercised for 45 minutes at 60% of their maximum heart rate with no snack given before exercise. During APX, insulin was decreased and glucagon was increased at exercise onset, while during SAP, subjects could adjust dosing before exercise. The two primary outcomes were percent of time in hypoglycemia (<3.9 mmol/L) and percent of time in euglycemia (3.9–10 mmol/L) from the start of exercise to the end of the study. Results The mean times spent in hypoglycemia (<3.9 mmol/L) after the start of exercise were 0.3% [−0.1, 0.7%] for APX, 3.1% [0.8, 5.3%] for APN, and 0.8% [0.1, 1.4%] for SAP. There was an absolute difference of 2.8% less time in hypoglycemia in APX versus APN (p =0.001) and 0.5% less time in hypoglycemia for APX versus SAP (p = 0.16). Mean time in euglycemia was comparable across conditions. Conclusions Adjusting insulin and glucagon delivery at exercise onset within a dual-hormone AP significantly reduces hypoglycemia compared with no adjustment and performs similarly to SAP when insulin is adjusted before exercise.

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In this article, we present several important contributions necessary for enabling an artificial endocrine pancreas (AP) system to better respond to exercise events. First, we show how exercise can be automatically detected using body-worn accelerometer and heart rate sensors. During a 22 hour overnight inpatient study, 13 subjects with type 1 diabetes wearing a Zephyr accelerometer and heart rate monitor underwent 45 minutes of mild aerobic treadmill exercise while controlling their glucose levels using sensor-augmented pump therapy. We used the accelerometer and heart rate as inputs into a validated regression model. Using this model, we were able to detect the exercise event with a sensitivity of 97.2% and a specificity of 99.5%. Second, from this same study, we show how patients’ glucose declined during the exercise event and we present results from in silico modeling that demonstrate how including an exercise model in the glucoregulatory model improves the estimation of the drop in glucose during exercise. Last, we present an exercise dosing adjustment algorithm and describe parameter tuning and performance using an in silico glucoregulatory model during an exercise event.

Acidosis is a common feature of human brain during ischemic stroke and is known to independently cause neuronal injury. However, the mechanism underlying acidosis-mediated injury of human brain remains elusive. We show that lowering the extracellular pH evoked inward currents characteristic of acid-sensing ion channels (ASICs) and increased intracellular Ca2+ in cultured human cortical neurons. ASICs in human cortical neurons show electrophysiological and pharmacological properties distinct from neurons in rodent brain. RT-PCR and Western blot detected high level of ASIC1a subunit with little or no expression of other ASIC subunits. Treatment of human cortical neurons with acidic solution induced substantial cell injury, which was attenuated by ASIC1a blockade. Thus, functional homomeric ASIC1a channels are predominantly expressed in neurons from human brain. Activation of these channels plays an important role in acidosis-mediated injury of human brain neurons.

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Acid-sensing ion channels (ASICs) are voltage-independent Na ؉ channels activated by extracellular protons. ASIC1a is expressed in neurons in mammalian brain and is implicated in long term potentiation of synaptic transmission that contributes to learning and memory. In ischemic brain injury, however, activation of this Ca 2؉ -permeable channel plays a critical role in acidosis-mediated, glutamate-independent, Ca 2؉ toxicity. We report here the identification of insulin as a regulator of ASIC1a surface expression. In modeled ischemia using Chinese hamster ovary cells, serum depletion caused a significant increase in ASIC1a surface expression that resulted in the potentiation of ASIC1a activity. Among the components of serum, insulin was identified as the key factor that maintains a low level of ASIC1a on the plasma membrane. Neurons subjected to insulin depletion increased surface expression of ASIC1a with resultant potentiation of ASIC1a currents. Intracellularly, ASIC1a is predominantly localized to the endoplasmic reticulum in Chinese hamster ovary cells, and this intracellular localization is also observed in neurons. Under conditions of serum or insulin depletion, the intracellular ASIC1a is translocated to the cell surface, increasing the surface expression level. These results reveal an important trafficking mechanism of ASIC1a that is relevant to both the normal physiology and the pathological activity of this channel.Acid-sensing ion channels belong to the epithelial sodium channel and degenerin family of ion channels and primarily transport Na ϩ into cells. ASICs 2 are activated by the presence of extracellular protons, which serve as ligands for these channels. So far six isoforms of ASICs (ASIC1a, 1b, 2a, 2b, 3, and 4) have been found in the mammalian central and peripheral nervous system. ASIC1a is expressed in various regions of brain including hippocampus, cerebral cortex, cerebellum, and amygdala (1-3). The role of ASIC1a in brain function is well characterized, in particular by electrophysiological and behavioral studies of ASIC1a knock-out (ASIC1aH ϩ -evoked currents are involved in synaptic transmission that contributes to important normal brain functions such as learning and memory in hippocampus and fear-related behaviors in the amygdala (3-5). Like other ASIC isoforms, the amino acid sequence of ASIC1a reveals a structure highly conserved among the epithelial sodium channel family (6). The crystal structure of a truncated chicken ASIC1a channel determined that this two-transmembrane protein is assembled as a trimer (7). Cerebral neurons express native ASIC1a as an assembly of homomultimers as well as heteromultimers in association with ASIC2a (8). Although ASIC1a and ASIC2a share high homology in their amino acid sequences, these proton-activated channels exhibit distinct sensitivity to extracellular pH. ASIC1a is more sensitive to changes in extracellular proton levels than ASIC2a and thus activates at a higher pH (pH of halfmaximal channel activation pH 0.5 ϭ 6.2), whereas ASIC2a activate...