Tatus is impaired, so the function of AMPK in regulating energy homeostasis might be compromised. The implication of those final results is that leptin concentration is very important to optimize the sensitivity of AMPK signaling to cellular power status, so AMPK could be sufficiently activated at fasting glucose levels and inhibited at fed glucose levels. We further determined the effects of glucose concentrations and leptin on RMPs (Fig. 5B). The results strikingly resemble these of pAMPK levels (Fig. 5C). Provided that RMPs have a linear connection to pAMPK levels (Fig. 5D) plus the surface levels of KATP channels are regulated by pAMPK levels (Fig. two), we propose a model in which the KATP channel trafficking mediated by AMPK will be the essential mechanism for regulating pancreatic cell RMPs in response to glucose concentration alterations. It generally is believed that the sensitivity on the pancreatic cell’s responses to glucose concentration changes will depend on the ATP sensitivity of KATP channel gating (2, 3). At low glucose concentrations, the open probability (PO) of KATP channels is enhanced by a rise in MgADP associated using a lower in ATP. However, at physiologically relevant glucose levels, KATP channels have really low PO (33, 34), and also the selection of PO change is narrow (in ref. 31, 7 and three of maximum PO in five mM and ten mM glucose, respectively). Therefore, it has beenPNAS | July 30, 2013 | vol. 110 | no. 31 |CELL BIOLOGYquestioned no matter if gating regulation of KATP channels by MgADP and ATP is adequate to induce glucosedependent membrane potential modifications in pancreatic cells. We showed that AMPKdependent KATP channel trafficking serves as yet another crucial mechanism for cell membrane potential regulation.3-(Trimethylsilyl)-2-propyn-1-ol Price We measured Kir6.1367777-12-5 web two surface density by Western blotting (Fig.PMID:33485668 two A ) and noise analysis (Fig. 2G) and showed that the improve in Kir6.two surface density by leptin is about threefold, which can be no much less than the dynamic range of PO changes by MgADP and ATP. The function of AMPK in pancreatic cell functions also is supported by a recent study working with mice lacking AMPK2 in their pancreatic cells, in which decreased glucose concentrations failed to hyperpolarize pancreatic cell membrane possible (35). Interestingly, glucosestimulated insulin secretion (GSIS) also was impaired by AMPK2 knockout (35), suggesting that the maintenance of hyperpolarized membrane prospective at low blood glucose levels is a prerequisite for standard GSIS. The study didn’t think about KATP channel malfunction in these impairments, but KATP channel trafficking pretty likely is impaired in AMPK2 in pancreatic cells, causing a failure of hyperpolarization at low glucose concentrations. It also is doable that impaired trafficking of KATP channels impacts cell response to high glucose stimulation, but this possibility remains to be studied. We also show the important role of leptin on KATP channel trafficking to the plasma membrane at fasting glucose concentrations in vivo (Fig. 1). These results are in line with our model that leptin is required for keeping sufficient density of KATP channels inside the cell plasma membrane, which guarantees proper regulation of membrane potential beneath resting conditions, acting mostly for the duration of fasting to dampen insulin secretion. In this context, hyperinsulinemia associated with leptin deficiency (ob/ob mice) or leptin receptor deficiency (db/db mice) could be explained by impaired tonic inhibition as a result of insufficient KATP channel density in the surface membrane. B.
