ABSTRACT Some, perhaps all, G protein-coupled receptors form homo-or heterodimers. We have shown that metabotropic glutamate receptors are covalent dimers, held together by one or more disulfide bonds near the N terminus. Here we report how mutating cysteines in this region affect dimerization and function. These results demonstrate that 1) covalent dimerization is not critical for mGlu 5 binding or function; 2) mGlu 5 remains a noncovalent dimer even in the absence of covalent dimerization; and 3) high-affinity binding requires Cys-57 and Cys-99. Many classes of receptors, such as the tyrosine kinaselinked receptors and the ligand-gated ion channels, function as di-or oligomeric assemblies of polypeptides. In contrast, G protein-coupled receptors (GPCRs) have traditionally been thought to exist and operate as monomers. This view has been changing. For example, early indirect evidence, from radiation inactivation target-size analysi
