L-Amino Acid Sensing by the Calcium Sensing Receptor

The human calcium sensing receptor (hCaR) is a G-protein coupled receptor that responds to calcium ions as its principal physiological agonist. L-amino acids are allosteric activators of the cloned CaR expressed in HEK293 cells but the physiological significance of this effect has been uncertain. This book provides evidence that L-amino acids are physiologically relevant activators of endogenous CaRs. Experiments reported in this book also investigated the location of amino acid binding site of the CaR. Chimeric receptors constructed by domain shuffling between the human CaR and rat metabotropic glutamate receptor type-1 (mGlu-1) were used to localize the amino acid binding site of the CaR to its N-terminal, bilobed, Venus Fly Trap domain. Furthermore, the roles of putative amino acid binding site residues in the Venus Fly Trap domain were investigated using conservative and semi-conservative mutations of the following residues: T145, S147, T151, S169, S170, S171, Y218 and E297. Finally, a novel activating mutation (E604K) in the cysteine rich domain of the hCaR in an Australian family with autosomal dominant hypocalcemia (ADH) was identified.