Promiscuous G-protein activation by the calcium-sensing receptor

The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca²⁺ concentration and maintains Ca²⁺ homeostasis^1,2. It also mediates diverse cellular processes not associated with Ca²⁺ balance^3-5. The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes⁶. We determined structures of CaSR in complex with G proteins from three different subfamilies: G_q, G_i and G_s. We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each Gα subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1-ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Gα. We identified a single Gα residue that determines G_q and G_s versus G_i selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Gα subtypes, thereby conferring capacity for promiscuous G-protein coupling.