Cab45b, a Munc18b-interacting Partner, Regulates Exocytosis in Pancreatic β-Cells

• Published in: The Journal of biological chemistry Vol. 284; no. 31; p. 20840
• Main Authors: Yi Zhang, You-hou Kang, Nathan Chang, Patrick P. L. Lam, Yunfeng Liu, Vesa M. Olkkonen, Herbert Y. Gaisano
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 31.07.2009
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.017467

Cab45b is a cytosolic Ca 2+ -binding protein reported to regulate zymogen secretion in pancreatic acini. We now show that Cab45b is also expressed in pancreatic islet β-cells and interacts there with the Sec1-Munc18 protein Munc18b. We employed patch clamp cell capacitance measurements to show that antibodies against Cab45b inhibited depolarization-evoked membrane capacitance increments, suggesting an impact on β-cell granule exocytosis, both the readily releasable granule pool and refilling of this pool. Site-specific mutants in the Cab45b EF-hands were used to dissect the molecular interactions involved in Cab45b function. Mutants in EF-hands 2 and 3 had no detectable effects on interaction of Cab45b with Munc18b and did not affect the depolarization-evoked calcium currents, but remarkably, they facilitated the complex formation of Munc18b with syntaxin-2 and -3. As a result, these two EF-hand mutants inhibited β-cell membrane capacitance increments. This inhibition is mediated via Munc18b because Munc18b silencing with small interfering RNA abolished the effects of these two mutants. The results suggest a mechanism for Cab45b action that involves regulating the dynamic association of Munc18b with SNAREs to impact β-cell granule exocytosis.