Navigating the duality of opioids' potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to mediate these contradictory effects. Here, we show that the fms-like tyrosine kinase receptor 3 (FLT3) in peripheral somatosensory neurons drives morphine tolerance and hyperalgesia in a male rodent model.
View Article and Find Full Text PDFAcute pain has been associated with persistent pain sensitization of nociceptive pathways increasing the risk of transition from acute to chronic pain. We demonstrated the critical role of the FLT3- tyrosine kinase receptor, expressed in sensory neurons, in pain chronification after peripheral nerve injury. However, it is unclear whether injury-induced pain sensitization can also promote long-term mood disorders.
View Article and Find Full Text PDFInhibiting receptor tyrosine kinases is commonly achieved by two main strategies targeting either the intracellular kinase domain by low molecular weight compounds or the extracellular ligand-binding domain by monoclonal antibodies. Identifying small molecules able to inhibit RTKs at the extracellular level would be highly desirable to gain exquisite selectivity but is believed to be challenging owing to the size of RTK endogenous ligands (cytokines, growth factors) and the topology of RTK extracellular domains. We here report the high-throughput screening of the French Chemical Library (48K compounds) for extracellular inhibitors of the Fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase, by a homogeneous time-resolved fluorescence competition assay.
View Article and Find Full Text PDFPeripheral neuropathic pain (PNP) is a debilitating and intractable chronic disease, for which sensitization of somatosensory neurons present in dorsal root ganglia that project to the dorsal spinal cord is a key physiopathological process. Here, we show that hematopoietic cells present at the nerve injury site express the cytokine FL, the ligand of fms-like tyrosine kinase 3 receptor (FLT3). FLT3 activation by intra-sciatic nerve injection of FL is sufficient to produce pain hypersensitivity, activate PNP-associated gene expression and generate short-term and long-term sensitization of sensory neurons.
View Article and Find Full Text PDFThe G protein-coupled receptor GHS-R1a mediates ghrelin-induced growth hormone secretion, food intake, and reward-seeking behaviors. GHS-R1a signals through Gq, Gi/o, G13, and arrestin. Biasing GHS-R1a signaling with specific ligands may lead to the development of more selective drugs to treat obesity or addiction with minimal side effects.
View Article and Find Full Text PDFHow G protein-coupled receptor conformational dynamics control G protein coupling to trigger signaling is a key but still open question. We addressed this question with a model system composed of the purified ghrelin receptor assembled into lipid discs. Combining receptor labeling through genetic incorporation of unnatural amino acids, lanthanide resonance energy transfer, and normal mode analyses, we directly demonstrate the occurrence of two distinct receptor:Gq assemblies with different geometries whose relative populations parallel the activation state of the receptor.
View Article and Find Full Text PDFDespite its central role in signaling and the potential therapeutic applications of inverse agonists, the molecular mechanisms underlying G protein-coupled receptor (GPCR) constitutive activity remain largely to be explored. In this context, ghrelin receptor GHS-R1a is a peculiar receptor in the sense that it displays a strikingly high, physiologically relevant, constitutive activity. To identify the molecular mechanisms responsible for this high constitutive activity, we have reconstituted a purified GHS-R1a monomer in a lipid disc.
View Article and Find Full Text PDFThe growth hormone secretagogue receptor type 1a (GHS-R1a) belongs to class A G-protein-coupled receptors (GPCR). This receptor mediates pleiotropic effects of ghrelin and represents a promising target for dysfunctions of growth hormone secretion and energy homeostasis including obesity. Identification of new compounds which bind GHS-R1a is traditionally achieved using radioactive binding assays.
View Article and Find Full Text PDFThe Timothy syndrome is a multisystem disorder associated with the mutation of a Gly residue (G402 or G406) in the Ca(v)1.2 Ca(2+) channel. G406 is localized at the end of the IS6 segment and just before the intracellular I-II loop, which is important for the regulation of channel inactivation and the binding of the Ca(v)beta subunit.
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