1. Intracortical inhibition in the human motor cortex has been previously demonstrated using paired-pulse transcranial magnetic stimulation (TMS) protocols at short intervals (1-6 ms; short interval intracortical inhibition, SICI) with a subthreshold conditioning pulse preceding a suprathreshold test pulse, and at long intervals (50-200 ms; long interval intracortical inhibition, LICI) with suprathreshold conditioning and test pulses.2. We investigated whether different circuits mediate these inhibitory phenomena and how they interact. In nine healthy volunteers, we applied TMS to the motor cortex and recorded motor evoked potentials from the first dorsal interosseous muscle.3. With increasing test pulse strength, LICI decreases but SICI tends to increase. There was no correlation between the degree of SICI and LICI.4. We tested the interactions between SICI and LICI. SICI was reduced or eliminated in the presence of LICI. Loss of SICI was seen even with a conditioning stimulus too weak to induce significant LICI.5. Our findings demonstrate that different cell populations mediate SICI and LICI. The results are consistent with the hypothesis that LICI inhibits SICI through presynaptic GABA B receptors. Testing of SICI in the presence of LICI may be a non-invasive way of evaluating inhibitory interactions in the human motor cortex.

Indinavir is a useful tool to assess different functional contributions of GLUT4 to glucose uptake in common models of skeletal muscle and adipocytes.

Insulin stimulates glucose uptake by recruiting glucose transporter 4 (GLUT4) from an intracellular pool to the cell surface through a mechanism that is dependent on phosphatidylinositol (PI) 3-kinase (PI3-K) and cortical actin remodeling. Here we test the hypothesis that insulin-dependent actin filament remodeling determines the location of insulin signaling molecules. It has been shown previously that insulin treatment of L6 myotubes leads to a rapid rearrangement of actin filaments into submembrane structures where the p85 regulatory subunit of PI3-K and organelles containing GLUT4, VAMP2, and the insulin-regulated aminopeptidase (IRAP) colocalize. We now report that insulin receptor substrate-1 and the p110␣ catalytic subunit of PI3-K (but not p110␤) also colocalize with the actin structures. Akt-1 was also found in the remodeled actin structures, unlike another PI3-K effector, atypical protein kinase C . Transiently transfected green fluorescent protein (GFP)-tagged pleckstrin homology (PH) domains of general receptor for phosphoinositides-1 (GRP1) or Akt (ligands of phosphatidylinositol-3,4,5-trisphosphate [PI-3,4,5-P 3 ]) migrated to the periphery of the live cells; in fixed cells, they were detected in the insulin-induced actin structures. These results suggest that PI-3,4,5-P 3 is generated on membranes located within the actin mesh. Actin remodeling and GLUT4 externalization were blocked in cells highly expressing GFP-PH-GRP1, suggesting that PI-3,4,5-P 3 is required for both phenomena. We propose that PI-3,4,5-P 3 leads to actin remodeling, which in turn segregates p85␣ and p110␣, thus localizing PI-3,4,5-P 3 production on membranes trapped by the actin mesh. Insulin-stimulated actin remodeling may spatially coordinate the localized generation of PI-3,4,5-P 3 and recruitment of Akt, ultimately leading to GLUT4 insertion at the plasma membrane.