A new pathway for cellular signaling is reported online in this week's Nature Chemical Biology. This report should have a major impact on understanding the how the largest class of drugs target the body's cells.

G-protein coupled receptors (GPCRs) are a class of proteins found on the cell membrane that are responsible for most of the communication between the outside and inside of the cell. It was thought that these receptors were only active on the cell surface, and would only enter a cell to be degraded and replaced by new GPCRs.

Jean-Pierre Vilardaga and colleagues now show that signaling of the one GPCR ? the parathyroid hormone ? can continue even when the protein moves into the cell. When this GPCR is bound to one of its ligands, the parathyroid hormone, it continues to send signals, even from the inside of the cell, thus making the overall signal last longer. This behavior does not happen when the receptor binds a different ligand, the parathyroid hormone-related peptide.

This unexpected behavior of GPCR signaling will require a change in how scientists think about cellular signaling, and may impact how we study drugs that target these important receptors.