VAMP4, short for vesicle-associated membrane protein 4, is a vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein. It plays crucial roles in multiple cellular processes, including membrane trafficking, neurotransmission, and maintaining cellular homeostasis. It is involved in pathways such as insulin regulation, neurotransmitter release, and fatty acid uptake, and is important for the structure and function of the Golgi apparatus [1,2,3,4]. Genetic models, especially KO mouse models, can be valuable for studying VAMP4's functions.

In pancreatic β cells, VAMP4 deficiency led to increased blood insulin levels and hyperresponsiveness to glucose. VAMP4-positive immature insulin secretory granules fuse with lysosomes, ensuring the breakdown of excess (pro)insulin and maintenance of intracellular insulin homeostasis [1]. In hippocampal neurons, VAMP4 is required for Ca²⁺-dependent spontaneous excitatory neurotransmission, and its retrieval-regulating residues and clathrin-mediated vesicle trafficking are essential for maintaining spontaneous release [2]. In muscle stem cells, the palmitoylation-facilitated formation of STX11/SNAP23/VAMP4 SNARE complex stimulates the fusion of CD36-and STX11-containing vesicles, promoting fatty acid uptake for muscle regeneration [3]. In HeLa cells, depletion of VAMP4 led to fragmentation of the Golgi ribbon, suggesting its role in maintaining the Golgi apparatus structure [4].

In conclusion, VAMP4 is essential for processes like insulin regulation, neurotransmission, fatty acid uptake, and maintaining Golgi structure. Studies using KO models have revealed its role in diabetes-related insulin regulation, and its potential as a target for diabetes treatment. Understanding VAMP4's functions provides insights into the underlying mechanisms of these biological processes and related diseases [1].