L-Amino Acid Sensing by the Calcium Sensing Receptor

The human calcium sensing receptor (hCaR) is aG-protein coupled receptor that responds to calciumions as its principal physiological agonist. L-aminoacids are allosteric activators of the cloned CaRexpressed in HEK293 cells but the physiologicalsignificance of this effect has been uncertain. Thisbook provides evidence that L-amino acids arephysiologically relevant activators of endogenousCaRs. Experiments reported in this book alsoinvestigated the location of amino acid binding siteof the CaR. Chimeric receptors constructed by domainshuffling between the human CaR and rat metabotropicglutamate receptor type-1 (mGlu-1) were used tolocalize the amino acid binding site of the CaR toits N-terminal bilobed Venus Fly Trap domain.Furthermore the roles of putative amino acid bindingsite residues in the Venus Fly Trap domain wereinvestigated using conservative and semi-conservativemutations of the following residues: T145 S147T151 S169 S170 S171 Y218 and E297. Finally anovel activating mutation (E604K) in the cysteinerich domain of the hCaR in an Australian family withautosomal dominant hypocalcemia (ADH) was identified.