Identification and Characterization of Two G Protein-coupled Receptors for Neuropeptide FF

Abstract

The central nervous system octapeptide, neuropeptide FF (NPFF), is believed to play a role in pain modulation and opiate tolerance. Two G protein-coupled receptors, NPFF1 and NPFF2, were isolated from human and rat central nervous system tissues. NPFF specifically bound to NPFF1 (K d ‫؍‬ 1.13 nM) and NPFF2 (K d ‫؍‬ 0.37 nM), and both receptors were activated by NPFF in a variety of heterologous expression systems. The localization of mRNA and binding sites of these receptors in the dorsal horn of the spinal cord, the lateral hypothalamus, the spinal trigeminal nuclei, and the thalamic nuclei supports a role for NPFF in pain modulation. Among the receptors with the highest amino acid sequence homology to NPFF1 and NPFF2 are members of the orexin, NPY, and cholecystokinin families, which have been implicated in feeding. These similarities together with the finding that BIBP3226, an anorexigenic Y1 receptor ligand, also binds to NPFF1 suggest a potential role for NPFF1 in feeding. The identification of NPFF1 and NPFF2 will help delineate their roles in these and other physiological functions.

Effects of pain controlling neuropeptides on human fat cell lipolysis

“…Detailed examinations of signal transduction can only be carried out in cell systems with stable manipulation of the expression of either or both of the receptors. [5][6][7][8][9]13,14 Unfortunately at present it is not possible to carry out such studies in human adipocytes kept in primary culture. We therefore used an indirect approach by comparing the effect of NPFF with that of NPSF and by using selective lipolysis agents acting on defined steps in signal transduction.…”

“…5 NPFF interacts with Gi/o-protein coupled receptors termed GPR74 and GPR147. [6][7][8][9] These two receptors may have specific roles in NPFF-action because they are differentially coupled to G-proteins. 10 After binding of NPFF (and related neuropeptides) to GPR it can induce stimulatory or inhibitory effects on the cyclic AMP system depending on how GPR is linked to the different G-proteins (G i , G s and G o ).…”

Identification of proNeuropeptide FFA peptides processed in neuronal and non‐neuronal cells and in nervous tissue

“…These pharmacological effects are mediated by two G-protein-coupled receptors, NPFF 1 and NPFF 2 , cloned in human and rat [22][23][24][25]. Pharmacological characterization of these receptors in recombinant cell lines showed a better selectivity of peptides deduced from proNPFF A sequence for NPFF 2 receptors binding, whereas proN-PFF B -derived peptides displayed a greater affinity for NPFF 1 receptors [26].…”

“…Recent data provided evidence that opioid and NPFF endogenous systems exert a tonic activity, NPFF counteracting tonic opioid analgesia under resting conditions [13]. NPFF is also implicated in morphine tolerance, morphine abstinence and also in several physiological processes, such as body thermoregulation, food intake and blood pressure regulation [7,[14][15][16][17][18][19][20][21].These pharmacological effects are mediated by two G-protein-coupled receptors, NPFF 1 and NPFF 2 , cloned in human and rat [22][23][24][25]. Pharmacological characterization of these receptors in recombinant cell lines showed a better selectivity of peptides deduced from proNPFF A sequence for NPFF 2 receptors binding, whereas proN-PFF B -derived peptides displayed a greater affinity for NPFF 1 receptors [26].…”

Neuropeptide AF and FF Modulation of Adipocyte Metabolism

“…Two human receptors for NPFF and NPAF have very recently been identified (14,16,17). The first reported human receptor for NPFF and NPAF, initially called HLWAR77, is a previous orphan 7-transmembrane domain G protein-coupled receptor, which when stably expressed in HEK293 exhibit similar nanomolar affinity for both NPAF and NPFF (14).…”