We propose that AgNPs interact with SR-B1 leading to recruitment of PDZK1 (SR-B1 adaptor protein), which activates downstream signaling cascade involving PI3K and PLCγ. Inositol 1,4,5-triphosphate (IP3), which is released following activation of PLCγ, interacts with its receptor IP3R on smooth endoplasmic reticulum (SER) leading to the release of Ca2+ from ER stores. As a result of a drop in Ca2+ levels in SER, the CRAC Ca2+ channels (cell membrane) are activated leading to influx of extracellular Ca2+. Increasing intracellular Ca2+ levels ([Ca2+]i) is ultimately culminated in mast cell degranulation. PKC: Protein kinase C; IP3 (InsP3): inositol triphosphate; PtdIns(4,5)P2: phosphatidylinositol-4,5-bisphosphate (PIP2); PtdIns(3,4,5)P3: phosphatidylinositol-3,4,5-Triphosphate (PIP3); PIP2 and PIP3 are membrane phospholipids; DAG: diacylglycerol. cSrc: cellular sarcoma (protein tyrosine kinase); TRPC: transient receptor potential cation channels.