|Start Date / Time||April 29, 2015 at 9:00 AM|
|End Date / Time||April 29, 2015 at 9:55 AM|
|Location||512 Light Hall|
|Presenter Name||Troy Hutchens (Piston's lab)|
|Presentation Title||EphA4-Mediated Juxtacrine Signaling Regulates Glucagon Secretion through Changes in F-Actin Density|
|Status||This meeting has already occurred|
The loss of inhibition of glucagon secretion exacerbates hyperglycemia in types 1 and 2 diabetes. However, the molecular mechanisms that regulate glucagon secretion in unaffected and diabetic states remain relatively unexplained. We present evidence supporting a new model of juxtacrine-mediated regulation of glucagon secretion where neighboring islet cells negatively regulate glucagon secretion through tonic stimulation of α-cell EphA receptors. Primarily through EphA4 receptors, this stimulation contributes to the maintenance of a dense F-actin network. In islets, additional stimulation and inhibition of endogenous EphA forward signaling results in inhibition and enhancement, respectively, of glucagon secretion, accompanied by an increase and decrease, respectively, in α-cell F-actin density. Sorted α-cells lack endogenous stimulation of EphA forward signaling from neighboring cells, resulting in enhanced basal glucagon secretion as compared to islets and the elimination of glucose-inhibition of glucagon secretion. Restoration of EphA forward signaling in sorted α-cells recapitulates both normal basal glucagon secretion and glucose-inhibition of glucagon secretion. Additionally, α-cell-specific EphA4-/- mice exhibit abnormal glucagon dynamics, and EphA4-/- α-cells contain less dense F-actin networks than EphA4+/+ α-cells. This juxtacrine-mediated model provides insight into the functional and dysfunctional regulation of glucagon secretion and opens up new therapeutic strategies for the clinical management of diabetes.