title: Mutated CaV2.1 channels dysregulate CASK/P2X3 signaling in mouse trigeminal sensory neurons of R192Q Cacna1a knock-in mice.
abstract: BACKGROUND
  ATP-gated P2X3 receptors of sensory ganglion neurons are important transducers of pain as they adapt their expression and function in response to acute and chronic nociceptive signals. The present study investigated the role of calcium/calmodulin-dependent serine protein kinase (CASK) in controlling P2X3 receptor expression and function in trigeminal ganglia from Cacna1a R192Q-mutated knock-in (KI) mice, a genetic model for familial hemiplegic migraine type-1.
  
  
  RESULTS
  KI ganglion neurons showed more abundant CASK/P2X3 receptor complex at membrane level, a result that likely originated from gain-of-function effects of R192Q-mutated CaV2.1 channels and downstream enhanced CaMKII activity. The selective CaV2.1 channel blocker ω-Agatoxin IVA and the CaMKII inhibitor KN-93 were sufficient to return CASK/P2X3 co-expression to WT levels. After CASK silencing, P2X3 receptor expression was decreased in both WT and KI ganglia, supporting the role of CASK in P2X3 receptor stabilization. This process was functionally observed as reduced P2X3 receptor currents.
  
  
  CONCLUSIONS
  We propose that, in trigeminal sensory neurons, the CASK/P2X3 complex has a dynamic nature depending on intracellular calcium and related signaling, that are enhanced in a transgenic mouse model of genetic hemiplegic migraine.
authors.affiliation: Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, Trieste 34136, Italy. Elsa.Fabbretti@ung.si.
authors.forename: Aswini
authors.initials: A
authors.lastname: Gnanasekaran
authors.forename: Tanja
authors.initials: T
authors.lastname: Bele
authors.forename: Swathi
authors.initials: S
authors.lastname: Hullugundi
authors.forename: Manuela
authors.initials: M
authors.lastname: Simonetti
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.forename: Andrea
authors.initials: A
authors.lastname: Nistri
authors.forename: Elsa
authors.initials: E
authors.lastname: Fabbretti
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D058477:Receptors, Purinergic P2X3 / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D012668:Trigeminal Ganglion / Q000166:cytology*
chemical_list: D020864:Calcium Channels, N-Type; D051528:Guanylate Kinases; D058477:Receptors, Purinergic P2X3; C106868:CASK kinases