Located at the inner leaflet of the plasma membrane (PM), phosphatidyl-inositol 4,5-bisphosphate [PI(4,5)P₂] composes only 1–2 mol% of total PM lipids. With its synthesis and turnover both spatially and temporally regulated, PI(4,5)P₂ recruits and interacts with hundreds of cellular proteins to support a broad spectrum of cellular functions. Several factors contribute to the versatile and dynamic distribution of PI(4,5)P₂ in membranes. Physiological multivalent cations such as Ca²⁺ and Mg²⁺ can bridge between PI(4,5)P₂ headgroups, forming nanoscopic PI(4,5)P₂–cation clusters. The distinct lipid environment surrounding PI(4,5)P₂ affects the degree of PI(4,5)P₂ clustering. In addition, diverse cellular proteins interacting with PI(4,5)P₂ can further regulate PI(4,5)P₂ lateral distribution and accessibility. This review summarizes the current understanding of PI(4,5)P₂ behavior in both cells and model membranes, with emphasis on both multivalent cation– and protein-induced PI(4,5)P₂ clustering. Understanding the nature of spatially separated pools of PI(4,5)P₂ is fundamental to cell biology.

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