title: Effects of LPS on P2X3 receptors of trigeminal sensory neurons and macrophages from mice expressing the R192Q Cacna1a gene mutation of familial hemiplegic migraine-1.
abstract: A knockin (KI) mouse model with the R192Q missense mutation in the Cacna1a gene commonly detected in familial hemiplegic migraine was used to study whether trigeminal ganglia showed a basal inflammatory profile that could be further enhanced by the lipopolysaccharide (LPS) toxin. Adenosine-5'-triphosphate (ATP)-gated purinergic ionotropic receptor 3 (P2X3) currents expressed by the large majority of trigeminal sensory neurons were taken as functional readout. Cultured R192Q KI trigeminal ganglia showed higher number of active macrophages, basal release of tumor necrosis factor alpha (TNFα), and larger P2X3 receptor currents with respect to wild type (WT) cells. After 5 h application of LPS in vitro, both WT and R192Q KI cultures demonstrated significant increase in macrophage activation, very large rise in TNFα mRNA content, and ambient protein levels together with fall in TNFα precursor, suggesting potent release of this inflammatory mediator. Notwithstanding the unchanged expression of P2X3 receptor protein in WT or R192Q KI cultures, LPS evoked a large rise in WT neuronal currents that recovered faster from desensitization. Basal R192Q KI currents were larger than WT ones and could not be further augmented by LPS. These data suggest that KI cultures had a basal neuroinflammatory profile that might facilitate the release of endogenous mediators (including ATP) to activate constitutively hyperfunctional P2X3 receptors and amplify nociceptive signaling by trigeminal sensory neurons.
authors: Department of Neuroscience and Italian Institute of Technology Unit, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy. alessia.franceschini@sissa.it
authors: Alessia
authors: A
authors: Franceschini
authors: Swathi K
authors: SK
authors: Hullugundi
authors: Arn M J M
authors: AM
authors: van den Maagdenberg
authors: Andrea
authors: A
authors: Nistri
authors: Elsa
authors: E
authors: Fabbretti
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics* / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D020325:Migraine with Aura / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D018408:Patch-Clamp Techniques; D060888:Real-Time Polymerase Chain Reaction; D058477:Receptors, Purinergic P2X3 / Q000187:drug effects*; D011984:Sensory Receptor Cells / Q000187:drug effects*; D012668:Trigeminal Ganglion / Q000166:cytology* / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; D008070:Lipopolysaccharides; D058477:Receptors, Purinergic P2X3; D014409:Tumor Necrosis Factor-alpha; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type