Regulation of Glut 1 Function

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DESCRIPTION (provided by applicant): Glut1 glucose transporter is an integral plasma membrane protein that is expressed in many cells and tissues. We have found that the acute (1-2 h) stimulation of Glut 1-mediated glucose transport is controlled by "activation "' of Glut1 transporters pre-existing in the plasma membrane. We have also found that a fraction of cell Glut 1 is bound by stomatin resulting in inhibition of Glut1 function. More recently we have made the novel observation that a significant fraction of Glut1, and virtually all of stomatin, reside in the cholesterol- and sphingolipid-rich detergent-resistant membranes (DRMs), and that a fraction of Glut l (but not stomatin) moves out of the DRMs upon stimulation of glucose transport in response to inhibition of oxidative phosphorylation. Based on our results we propose that Glut 1 localized in the plasma membrane exists in two-states, namely inactive and active. This proposal will be tested by the following Specific Aims: 1) Test the hypothesis that association of stomatin and Glutl leads to inhibition of Glut1 function, 2) Test the hypothesis that Glutl dissociates from stomatin during its activation in response to inhibition of oxidative phosphorylation and following stimulation of AMP-activated protein kinase (AMPK), 3) Test the hypothesis that Glut l present in plasma membrane DRMs are palmitoylated and the movement of Glutl out of this micro-domain reflects its de-palmitoylation, and 4) Identify Glutl-binding proteins under basal and stimulated conditions. An understanding of the molecular events leading to control of Glut l function should provide new insights into potentially novel physiological and pharmacological regulators of this important transporter.