P2X3 receptors are predominantly expressed on sensory ganglion neurons where they play an important role in transducing pain signals[
1]. A major property of these receptors is the ability to rapidly adapt their function to extracellular milieu changes by trafficking-mediated receptor redistribution, by modulation of receptor function through intracellular kinases, or by interaction with specific scaffold proteins[
2‐
5]. We recently reported that under basal conditions P2X3 receptors are strongly associated with the multifunction scaffold protein calcium/calmodulin-dependent serine protein kinase (CASK)[
6]. In the present study we investigated whether the CASK/P2X3 complex was altered and functionally linked to sensitization of P2X3 receptors in transgenic knock-in (KI) mice exhibiting a gain-of-function phenotype of voltage-gated Ca
V2.1 (P/Q-type) calcium channels, due to a R192Q missense mutation in the channel α1 subunit that causes familial hemiplegic migraine type 1 (FHM-1)[
7,
8]. Using this KI mouse model, we previously identified multiple Ca
V2.1 channel interactors (calcineurin, Cdk5 and CaMKII) that modulate P2X3 receptor function in trigeminal sensory neurons[
9‐
12]. In particular, enhanced P2X3 receptor-mediated responses were found in KI neurons that depend on constitutive activation of CaMKII and are reversed by the selective Ca
V2.1 channel blocker or by the CaMKII inhibitor[
9]. Previous studies showed that CASK is associated with calcium channels[
13‐
15] and, thus, provide the rational to explore if the R192Q mutation in KI mice influences CASK/P2X3 assembly and function. The present study aimed at testing, with molecular biology and electrophysiological methods, the properties of the CASK/P2X3 receptor complex in this mouse model expressing gain-of-function of Ca
V2.1 channels, using primary cultures of trigeminal ganglia that fully retain the basal characteristics of the CASK/P2X3 complex
in vivo[
6].