L-cysteine sulfinic acid as an endogenous agonist of a novel metabotropic receptor coupled to stimulation of phospholipase D activity

A substantial body of research implicates L-cysteine sulfinic acid (L-CSA) as a neurotransmitter. However, all physiological actions of L-CSA that have been pharmacologically characterized are mediated by cross-activation of glutamate receptors, and no receptor has been identified that is primarily activated by L-CSA. We report that a receptor exists in adult rat hippocampus that is activated by L-CSA but is insensitive to several Other endogenous excitatory Amino acids (EAAs), including L-glutamate, L-aspartate, and L-homocysteic acid. This receptor is coupled to an increase in the activity of Phospholipase D (PLD). The L-CSA-induced PLD response is not blocked by ionotropic glutamate receptor antagonists but is mimicked by the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid. The agonist pharmacology of the PLD-coupled response is generally similar to that of mGluRs but clearly differs from that of any particular mGluR that has been characterized to date. Furthermore, this receptor is not significantly blocked by (RS)-alpha-methyl-4-carboxyphenylglycine, which blocks a variety of mGluR-mediated responses. L-CSA has little effect on mGluRs coupled to phosphoinositide hydrolysis or the potentiation of cAMP responses in adult hippocampus, indicating that L-CSA is not a broad mGluR Agonist. It is commonly thought that EAAs act on the same receptor families, all of which use glutamate as their primary agonist. However, the finding that L-CSA acts on a glutamate-insensitive receptor suggests that different receptor families might exist for different EAAs.