Nutrient Sensing

Summary:

GPRC6a is an extracellular receptor and nutrient sensor that binds L-α amino acids, particularly basic amino acids including L-arginine (high affinity), ornithine (high affinity), and L-lysine possibly through the Gq subunit. Recent work including data from our lab that suggest that GPRC6a signals to the mechanistic target of rapamycin complex (mTORC1). We hypothesize that decreased signaling of GPRC6a activates autophagy and tau clearance. We posit that GPRC6a receives tonic extracellular stimulation and senses the amino acids abundance, via L-arginine or derivative-like amino acids. Genetic targeting of GPRC6a essentially reduces the efficacy and functionality of the receptor, thereby nullifying endogenous ligands ineffective and signaling “amino acid deficiency” inducing autophagy. Recently, GPRC6a receptor variants have been identified in different ethnic populations that alter receptor trafficking and perhaps signaling. Imbalanced signaling could lead to loss or gain of function which could impact diseases that affect nutrient sensing and mTORC signaling in certain ethic populations. Cellular arginine sensor for mTORC1 (CASTOR1) a negative regulator of mTORC1 and SLC23A9, a positive regulator of mTORC1 have also recently been identified. Arginine sensing dysfunction have been identified in chronic diseases. Our lab studies how these nutrient sensors can be tuned to regulate proteostasis.