Extracellular calcium-sensing receptor
phospholipase C-activating G protein-coupled receptor signaling pathway
Promiscuous G-protein activation by the calcium-sensing receptor.
The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca<sup>2+</sup> concentration and maintains Ca<sup>2+</sup> homeostasis<sup>1,2</sup>. It also mediates diverse cellular processes not associated with Ca<sup>2+</sup> balance<sup>3-5</sup>. The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes<sup>6</sup>. We determined structures of CaSR in complex with G proteins from three different subfamilies: G<sub>q</sub>, G<sub>i</sub> and G<sub>s</sub>. 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<sub>q</sub> and G<sub>s</sub> versus G<sub>i</sub> selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Gα subtypes, thereby conferring capacity for promiscuous G-protein coupling.