Medical School
Twin Cities
The neurotensin receptor 1 (NTSR1) is a G protein-coupled receptor (GPCR) that acts as a modulator of brain dopamine signaling and affects body temperature. NTSR1 ligands have been under clinical development for diverse conditions, including substance use disorders, schizophrenia, and small cell lung cancer. Systemic and central administration of peptide NTSR1 agonists in rodent models produces profound hypothermia. This effect is not desirable during treatment of psychiatric disorders, but may be therapeutically beneficial in promoting acute neuroprotection following stroke and ischemic injury. A determination of the mechanism by which NTSR1 activation reduces body temperature will facilitate both focused psychiatric drug development that avoids hypothermia and neuroprotection drug development that leverages the hypothermic effect.
GABA-ergic neurons in the preoptic area of the hypothalamus were recently identified as the critical cell population mediating NTSR1 agonist-induced hypothermia in the mouse. The signaling pathway NTSR1 triggers within these cells to induce hypothermia remains unknown. G protein-coupled receptors in the brain can activate one or more of 13 non-visual G proteins. These proteins mediate distinct cellular and physiological effects. NTSR1 is a notoriously promiscuous receptor, activating at least 12 different G proteins in cultured cells. To determine which signaling pathways NTSR1 may activate to lower body temperature, these researchers sought to determine which G proteins are expressed in NTSR1-expressing GABA-ergic neurons in the preoptic area of the mouse. Their findings suggest that the population of cells upon which NTSR1 ligands act in the medial preoptic area is much smaller than anticipated. The group's G protein expression profile of these cells significantly narrows the signaling pathways responsible for NTSR1-mediated hypothermia. Future work will build upon this work and use G protein-selective pharmacologic and genetic inhibition strategies to determine which of these identified proteins contribute to NTSR1-mediated hypothermia. This work furthers our understanding of how the neurotensin system regulates body temperature and will facilitate the development of safer, targeted NTSR1 therapeutics.