Abstract
Huntingtin-associated protein 1 (Hap1) was originally identified as a protein that binds to the Huntington disease protein, huntingtin. Growing evidence has shown that Hap1 participates in intracellular trafficking via its association with various microtubule-dependent transporters and organelles. Recent studies also revealed that Hap1 is involved in exocytosis such as insulin release from pancreatic β-cells. However, the mechanism underlying the action of Hap1 on insulin release remains to be investigated. We found that Hap1 knock-out mice had a lower plasma basal insulin level than control mice. Using cultured pancreatic β-cell lines, INS-1 cells, we confirmed that decreasing Hap1 reduces the number of secreted vesicles and inhibits vesicle exocytosis. Electrophysiology and imaging of intracellular Ca2+ measurements demonstrated that Hap1 depletion significantly reduces the influx of Ca2+ mediated by L-type Ca2+ channels (Cav). This decrease is not due to reduced expression of Cav1.2 channel mRNA but results from the decreased distribution of Cav1.2 on the plasma membrane of INS-1 cells. Fluorescence recovery after photobleaching showed a defective movement of Cav1.2 in Hap1 silencing INS-1 cells. Our findings suggest that Hap1 is important for insulin secretion of pancreatic β-cells via regulating the intracellular trafficking and plasma membrane localization of Cav1.2, providing new insight into the mechanisms that regulate insulin release from pancreatic β-cells.
Highlights
Huntingtin-associated protein 1 (Hap1) was originally identified as a protein that binds to the Huntington disease protein, huntingtin
Because Hap1Ϫ/Ϫ mice have retarded growth and die 3– 4 days after birth, and Hap1ϩ/Ϫ heterozygous mice showed no obvious behavioral and body weight abnormalities to wild-type mice and lived as long as WT mice [36], we focused our studies on Hap1Ϫ/Ϫ 3– 4-day-old mice to investigate the role of Hap1 in insulin secretion
The results showed that the insulin level of KO mice was significantly lower than WT mice (Fig. 1A, upper panel), indicating that lack of Hap1 may impair insulin release in mice
Summary
Huntingtin-associated protein 1 (Hap1) was originally identified as a protein that binds to the Huntington disease protein, huntingtin. Mutant huntingtin was found to interact with -tubulin and disrupt vesicular transport and insulin secretion [9] Given these findings, it would be interesting to investigate how Hap is involved in insulin release in pancreatic -cells. Down-regulation of Cav channel activity and/or density causes less insulin secretion and glucose intolerance, which is associated with a group of type 2 diabetic patients (26 –29). Whether and how Hap regulates the trafficking or surface expression of L-type Ca2ϩ channel in endocrine cells have not been reported. These data suggest that Hap plays an important role in regulation of insulin secretion in -cells and offer a new therapeutic target for ameliorating metabolic disorders due to defective insulin release from pancreatic -cells
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