Glucose stimulation for insulin movement
During a meal, beta cells in the pancreas respond to the rise in glucose level in the bloodstream. The insulin is carried in so-called large dense core vesicles (LDCVs) and problems with transport and fusion of these vesicles is one of the reasons behind type 2 diabetes. The recent studies of the 'Regulation of glucose-stimulated secretory vesicle mobilisation in pancreatic beta-cells' (Insulin Secretion) project have shown that motor proteins like kinesin drive the movement of LDCVs. The consortium aimed to investigate the mobilisation of the vesicles from the storage pool in the cell to release sites at the beta cell plasma membrane. One such motor protein under investigation was myosin Va. The brain-spliced isoform of myosin Va (BR-MyoVa) is essential for transport of hormones in secretory granules (SGs) in most secretory cells. Although the nature of the protein complex that recruits BR-MyoVa to to SG's for their transport is unknown, the Insulin Secretion project identified several binding protein partners that are involved with this process. These include granuphilin-a/b, Rab27a and rabphilin-3A. The study indicates there are many binding partners of BR-MyoVa to regulate SG movement. Evidence for multiple novel binding partners of BR-MyoVa also came with the discovery of MyRIP that seems to be important for stabilising MyoVa. MyRIP acts as a scaffolding protein that links protein kinase A (PKA) to the SGs. Another piece of the puzzle came with the evidence that the metabolic enzyme ATP-citrate lyase (ACL) also plays a part in insulin secretion. ACL is an important enzyme for glucose metabolism. Moreover the team showed that ACL is able to translocate to vesicles in a glucose-dependent manner and is a probable first as an example of a clear link between metabolism and LDCV movement in beta cells. For future research, the Insulin Secretion project scientists have produced a phosphorylation mutant of Rph-3A, an interacting partner of MyoVa. The impact of Rph-3A on hormone secretion will be investigated. Project results give details of molecules crucial to the secretion in response to glucose. Knowledge of the specific molecular actors responsible in the cascades promises to lead research closer to more targeted drug therapies for metabolic diseases like type 2 diabetes.
