Commentary: GPR160 De-Orphanization Reveals Critical Roles in Neuropathic Pain in Rodents (Finally, a Receptor for CART Peptide)

1. Abstract The discovery of the CART transcript and peptides implicated CART peptide (CARTp) as a neurotransmitter involved in the action of psychostimulants and several other physiological processes, buttressing the importance of the CARTp system. While there is evidence that a receptor(s) for CARTp exists, the receptor(s) has/have not been cloned. To understand how CARTp functions, it is important to identify its receptor(s). Given the evidence that CARTp receptor is a GPCR, a reasonable approach to searching for a CARTp receptor is to closely examine GPCR orphan receptors, receptors for which there are no known neurotransmitters. One of such GPCR orphan receptors that may be linked directly to CARTp function is GPR160. While studying neuropathic pain, Yosten et al (2020) identified CARTp effects were related to GPR160 expression. While studying food and water intake, Haddock et al (2021) also determined that the effects of CARTp were blocked by immuno-neutralization of GPR160. These findings suggest that the orphan receptor GPR160 may be the elusive CARTp receptor, a welcome observation after so many years of searching. This important discovery will advance the understanding of the CARTp system, including facilitating drug screening for small molecule agonists and antagonists and the identification of therapeutic compounds.