English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background  The R192Q mutation of the CACNA1A gene, encoding for the α1 subunit of voltage-gated P/Q Ca 2+  channels (Ca v 2.1), is associated with familial hemiplegic migraine-1. We investigated whether this gain-of-function mutation changed the structure and function of trigeminal neuron P2X 3  receptors that are thought to be important contributors to migraine pain.    Results  Using in vitro trigeminal sensory neurons of a mouse genetic model knockin for the CACNA1A R192Q mutation, we performed patch clamp recording and intracellular Ca 2+  imaging that showed how these knockin ganglion neurons generated P2X 3  receptor-mediated responses significantly larger than wt neurons. These enhanced effects were reversed by the Ca v 2.1 blocker ω-agatoxin. We, thus, explored intracellular signalling dependent on kinases and phosphatases to understand the molecular regulation of P2X 3  receptors of knockin neurons. In such cells we observed strong activation of CaMKII reversed by ω-agatoxin treatment. The CaMKII inhibitor KN-93 blocked CaMKII phosphorylation and the hyperesponsive P2X 3  phenotype. Although no significant difference in membrane expression of knockin receptors was found, serine phosphorylation of knockin P2X 3  receptors was constitutively decreased and restored by KN-93. No change in threonine or tyrosine phosphorylation was detected. Finally, pharmacological inhibitors of the phosphatase calcineurin normalized the enhanced P2X 3  receptor responses of knockin neurons and increased their serine phosphorylation.    Conclusions  The present results suggest that the CACNA1A mutation conferred a novel molecular phenotype to P2X 3  receptors of trigeminal ganglion neurons via CaMKII-dependent activation of calcineurin that selectively impaired the serine phosphorylation state of such receptors, thus potentiating their effects in transducing trigeminal nociception.

molecular pain

Familial Hemiplegic Migraine Ca<sub>V</sub>2.1 Channel Mutation R192Q Enhances ATP-gated P2X<sub>3</sub> Receptor Activity of Mouse Sensory Ganglion Neurons Mediating Trigeminal Pain

Familial Hemiplegic Migraine CaV2.1 Channel Mutation R192Q Enhances ATP-gated P2X3 Receptor Activity of Mouse Sensory Ganglion Neurons Mediating Trigeminal Pain

Familial Hemiplegic Migraine Ca_V2.1 Channel Mutation R192Q Enhances ATP-gated P2X₃ Receptor Activity of Mouse Sensory Ganglion Neurons Mediating Trigeminal Pain