Philippe Walker

The receptor for the orexigenic peptide melanin-concentrating hormone is a G-protein-coupled receptor

Gene-knockout studies of melanin-concentrating hormone (MCH) and its effect on feeding and energy balance have firmly established MCH as an orexigenic (appetite-stimulating) peptide hormone. Here we identify MCH as the ligand for the orphan receptor SLC-1. The rat SLC-1 is activated by nanomolar concentrations of MCH and is coupled to the G protein Gαi/o. The pattern of SLC-1 messenger RNA expression coincides with the distribution of MCH-containing nerve terminals and is consistent with the known central effects of MCH. Our identification of an MCH receptor could have implications for the development of new anti-obesity therapies.

Expression of thyrotropin-releasing hormone receptor 2 (TRH-R2) in the central nervous system of rats

The distribution of the recently discovered thyrotropin‐releasing hormone (TRH) receptor subtype TRH‐R2 was studied in rat brain, pituitary, and spinal cord by in situ hybridization histochemistry and compared with the distribution patterns of the other elements of TRH signaling, namely TRH, TRH‐R1, and the TRH‐degrading ectoenzyme (TRH‐DE). In contrast to the very restricted mRNA expression of TRH‐R1 in the central nervous system, TRH‐R2 mRNA was widely distributed with highest transcript levels throughout the thalamus, in the cerebral and cerebellar cortex, medial habenulae, medial geniculate nucleus, pontine nuclei, and throughout the reticular formation. In accordance with the well‐known endocrine function of TRH, TRH‐R1 is found predominantly expressed in hypothalamic regions. Expression of TRH‐R1 in various brainstem nuclei and spinal cord motoneurons seems to be associated with the described effects of TRH on the vegetative and autonomic system as well as on the somatomotor system. Furthermore, the fully complementary expression of both receptor subtypes, even in regions where transcripts for both receptors were found (e.g., medial septum, lateral hypothalamus superior colliculi, substantia nigra, etc.), indicates that in discrete neuroanatomical pathways the two receptors serve highly specific functions for the transmission of TRH signals. Together with TRH‐DE, the putative terminator of TRH actions that shows in various, but not all, brain areas, an overlapping mRNA distribution pattern with both receptors, the distribution of TRH‐R2 mRNA seems to provide the anatomical basis for the described effects of TRH on higher cognitive functions as well as its effect on arousal, locomotor activity, and pain perception. J. Comp. Neurol. 428:319–336, 2000.

Opioid receptor random mutagenesis reveals a mechanism for G protein-coupled receptor activation.

The high resolution structure of rhodopsin has greatly enhanced current understanding of G protein–coupled receptor (GPCR) structure in the off-state, but the activation process remains to be clarified. We investigated molecular mechanisms of δ-opioid receptor activation without a preconceived structural hypothesis. Using random mutagenesis of the entire receptor, we identified 30 activating point mutations. Three-dimensional modeling revealed an activation path originating from the third extracellular loop and propagating through tightly packed helices III, VI and VII down to a VI-VII cytoplasmic switch. N- and C-terminal determinants also influence receptor activity. Findings for this therapeutically important receptor may apply to other GPCRs that respond to diffusible ligands.