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Chapter 5 – Receptors Part 1 – Types of Receptors Video Clip – Receptor Superfamilies Receptors are protein switches that control biochemical processes in a cell. The switches are turned on through the binding of molecules called ligands. Much as a substrate binds an enzyme to trigger a reaction, a ligand reversibly attaches to a binding site on a receptor protein to activate a process. Ligands themselves can be divided into two categories: endogenous and exogenous. Endogenous ligands are the natural ligands found in the body that bind a receptor. Exogenous are unnatural compounds, often drugs, that bind a receptor. Receptors are classed into superfamilies, of which there are four: ligand-gated ion channels, G-protein-coupled receptors, tyrosine kinase-linked receptors, and nuclear receptors. Ligand-gated ion channels (LGICs) are large receptor proteins that span a cell membrane. When the proper ligand binds an ion channel, the channel opens and ions of the type specified by the channel are allowed to pass across the cell membrane and the cell membrane undergoes depolarization. Ligands that bind an ion channel and cause depolarization are often neurotransmitters and act upon neurons. In the case of ion channels, the ligand-binding event leads directly to depolarization. Neurotransmitters that act on ion channels are therefore called fast neurotransmitters. G-Protein-coupled receptors (GPCRs) are also cell membrane-spanning receptor proteins, but GPCRs do not form a channel across the membrane. GPCRs instead provide a means of communication across the membrane. When a ligand binds on the extracellular side of a GPCR, the conformation of the receptor protein changes on the intracellular side of the GPCR. The conformation change causes the release of bound proteins into the cytosol. These released proteins transmit the signal of the ligand and ultimate cause a cellular change through a series of steps. Because the ligand binding event so distant from the eventual cellular response, neurotransmitters that act on GPCRs are called slow neurotransmitters. Tyrosine kinase-linked receptors (TKLRs) also span the cell membrane. The binding of a ligand on the extracellular side of a TKLR causes two TLKRs to combine into a supramolecular complex. Key amino acids (tyrosines) in the complex are phosphorylated, and the entire complex becomes able to bind key proteins on the intracellular side of the receptor. The key proteins then propagate the extracellular ligand signal into the cell. TKLRs are associated with many growth factors and therefore with many cancer pathways when cellular regulation fails. Nuclear receptors are not bound to the cell membrane and instead are found free in the cell nucleus. The binding a nuclear receptors impacts many aspects of DNA regulation and gene expression. The binding of a nuclear receptor by a drug can have broad and difficult to control consequences within a cell. Nuclear receptor drugs often have a long list of potential side effects.

MOOC Medicinal Chemistry