Tracking nanoscale vesicles in diabetes and disease

Large dense core (LDC) vesicles are tiny intracellular organelles responsible for storing and releasing essential chemical messengers that regulate various bodily functions. LDC vesicles in neurons contain neurotransmitters and those in pancreatic beta cells contain insulin. Any abnormalities in the release of such vesicles can alter cellular chemical signals, leading to neurodegenerative disorders and diabetes, respectively.

Typically, LDC vesicles release their contents during a process called exocytosis. During exocytosis, fusion and lipid mixing between lipids in the vesicle membrane and the plasma membrane lead to the formation of a dilated pore before the release of content. This pore can either remain open – leading to complete fusion and release of vesicle cargo – or close after allowing only small molecules to exit. The messengers or small molecules that exit the vesicle then enter the extracellular space or bloodstream. This transient pore that is formed due to lipid mixing is called a fusion pore. Many proteins participate in the formation of the fusion pore and exocytosis. Lipids such as PIP2 have been shown to play a significant due to their increased concentration at the site of pore formation. However, studying the effect of PIP2 on vesicle membrane properties has been challenging.

Researchers at the Department of Developmental Biology and Genetics (DBG), led by Nikhil Gandasi, have employed a novel technique to investigate the impact of elevated PIP2 levels on the membranes of isolated LDC vesicles. The technique, called as the VIEC technique, uses ultra-microelectrodes that help in both quantitative and dynamic studies. The experiments provide a better resolution than existing techniques to monitor these nanoscale processes.

The results show that higher levels of PIP2 can modulate fusion pore properties, and confirm that this PIP2 modulation plays an important role in the exocytosis release. Consequently, this may change exocytosis dynamics and chemical messenger secretion yield in different neuronal and non-neuronal cells. This has wider implications for designing drugs for neurotransmitter release and possibly insulin release. Such advancements can open the door to novel therapies for neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS, as well as diabetes.

REFERENCE:
Makam AA, Wahlund J, Gandasi NR, Hatamie A, Single-vesicle microelectroanalysis reveals the role of PIP2 phospholipid in vesicle opening dynamics and its potential role in exocytosis, ACS Omega (2025).

https://doi.org/10.1021/acsomega.5c00864

LAB WEBSITE:
https://dbg.iisc.ac.in/people/nikhil-gandasi/