A primer on resolving the nanoscale structure of the plasma membrane with light and electron microscopy

The plasma membrane separates a cell from its external environment. All materials and signals that enter or leave the cell must cross this hydrophobic barrier. Understanding the architecture and dynamics of the plasma membrane has been a central focus of general cellular physiology. Both light and electron microscopy have been fundamental in this endeavor and have been used to reveal the dense, complex, and dynamic nanoscale landscape of the plasma membrane. Here, I review classic and recent developments in the methods used to image and study the structure of the plasma membrane, particularly light, electron, and correlative microscopies. I will discuss their history and use for mapping the plasma membrane and focus on how these tools have provided a structural framework for understanding the membrane at the scale of molecules. Finally, I will describe how these studies provide a roadmap for determining the nanoscale architecture of other organelles and entire cells in order to bridge the gap between cellular form and function.