Membrane potential regulates G-protein coupled receptors: role in ligand bias

G-protein coupled receptors (GPCRs) do not only signal via the canonical pathway, but they can also signal via G-protein independent pathways. To complicate the signaling mechanism further, some GPCR ligands show a bias: they can for instance act as antagonists in the G protein-dependent pathway but act as agonists in the independent pathway. GPCRs can also display signaling bias whereby different ligands activate different signaling pathways. The induced response of a similar GPCR can therefore differ significantly depending on the environment. Consequently, GCPRs of the same type do not always respond similarly as their conformational state is not alike between cell
types. Since GPCRs span the membrane they can also sense membrane voltage. Although several GPCRs display a voltage dependence in their ligand response, this parameter is not routinely included when studying the pharmacology of GPCRs.