The extracellular calcium-sensing human Ca2+ receptor (hCaR), a member of the family-3 G-protein-coupled receptors (GPCR) possesses a large amino-terminal extracellular ligand-binding domain (ECD) in addition to a seven transmembrane helical domain (7TMD) characteristic of all GPCRs. Two calcimimetic allosteric modulators, NPS R-568 and Calindol, that bind the 7TMD of the hCaR have been reported to potentiate the Ca2+ activation without independently activating the wild type receptor. Because agonists activate rhodopsin-like family-1 GPCRs by binding within the 7TMD, we examined the ability of Calindol, a novel chemically distinct calcimimetic, to activate a Ca2+ receptor construct (T903-Rhoc) in which the ECD and carboxyl-terminal tail have been deleted to produce a rhodopsin-like 7TMD. Here we report that although Calindol has little or no agonist activity in the absence of extracellular Ca2+ for the ECD-containing wild type or carboxyl-terminal deleted receptors, it acts as a strong agonist of the T903-Rhoc. In addition, Ca2+ alone displays little or no agonist activity for the hCaR 7TMD, but potentiates the activation by Calindol. We confirm that the activation of T903-Rhoc by Calindol is truly Ca2+-independent using in vitro reconstitution with purified Gq. These findings demonstrate distinct allosteric linkages between Ca2+ site(s) in the ECD and 7TMD and the 7TMD site(s) for calcimimetics.