BACKGROUND: Signaling by transmembrane receptors such as G protein-coupled 
receptors (GPCRs) occurs at the cell surface and throughout the endocytic 
pathway, and signaling from the cell surface may differ in magnitude and 
downstream output from intracellular signaling. As a result, the rate at which 
signaling molecules traverse the endocytic pathway makes a significant 
contribution to downstream output. Modulation of the core endocytic machinery 
facilitates differential uptake of individual cargoes. Clathrin-coated pits are 
a major entry portal where assembled clathrin forms a lattice around 
invaginating buds that have captured endocytic cargo. Clathrin assembles into 
triskelia composed of three clathrin heavy chains and associated clathrin light 
chains (CLCs). Despite the identification of clathrin-coated pits at the cell 
surface over 30 years ago, the functions of CLCs in endocytosis have been 
elusive.
RESULTS: In this work, we identify a novel role for CLCs in the regulated 
endocytosis of specific cargoes. Small interfering RNA-mediated knockdown of 
either CLCa or CLCb inhibits the uptake of GPCRs. Moreover, we demonstrate that 
phosphorylation of Ser204 in CLCb is required for efficient endocytosis of a 
subset of GPCRs and identify G protein-coupled receptor kinase 2 (GRK2) as a 
kinase that can phosphorylate CLCb on Ser204. Overexpression of CLCb(S204A) 
specifically inhibits the endocytosis of those GPCRs whose endocytosis is 
GRK2-dependent.
CONCLUSIONS: Together, these results indicate that CLCb phosphorylation acts as 
a discriminator for the endocytosis of specific GPCRs.