A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1

Hullugundi, Swathi K.; Ansuini, Alessio; Ferrari, Michel D.; Maagdenberg, Arn M. J. M. van den; Nistri, Andrea

doi:10.1016/j.neuroscience.2014.02.020

Cited by 25 publications

(32 citation statements)

References 45 publications

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“…Many triggers of migraine in human also activate TG meningeal nociceptors in rodents (Levy and Strassman 2004;Strassman et al 1996;Zhang et al 2010). Furthermore, mutations of the P/Q-type voltage-gated Ca 2ϩ channel associated with familial hemiplegic migraine type-1 cause hyperexcitation of TG neurons, suggesting that migraine headache may result from abnormal membrane conductance changes of the primary af- ferent neurons in TG (Fioretti et al 2011;Hullugundi et al 2014;Tao et al 2012). We reason that the effects of TRESK mutations/variants on TG excitability would be a better predictor of their contributions to migraine susceptibility, relative to their effects on TRESK currents in heterologous expression systems.…”

Section: Discussionmentioning

confidence: 99%

“…This calls into question a direct causal relationship between TRESK dysfunction and migraine phenotype (Andres-Enguix et al 2012;Eising et al 2013;Lafreniere et al 2010). On the other hand, previous works have illustrated the importance of studying migraine-associated gene mutations in neurons involved in migraine pathophysiology (Fioretti et al 2011;Hullugundi et al 2014;Liu et al 2013;Tao et al 2012;Tottene et al 2009;van Den Maagdenberg et al 2004). While the Xenopus oocyte system is a powerful tool for ion channel research, it may have limitations in predicting the genotype-phenotype correlation between TRESK mutations/variants and migraine susceptibility.…”

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confidence: 99%

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Nonmigraine-associated TRESK K⁺ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

Guo

Liu

Ren

et al. 2014

Journal of Neurophysiology

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Guo Z, Liu P, Ren F, Cao YQ. Nonmigraine-associated TRESK K ϩ channel variant C110R does not increase the excitability of trigeminal ganglion neurons. J Neurophysiol 112: 568 -579, 2014. First published May 7, 2014 doi:10.1152/jn.00267.2014.-Recent genetic studies suggest that dysfunction of ion channels and transporters may contribute to migraine pathophysiology. A migraineassociated frameshift mutation in the TWIK-related spinal cord K ϩ (TRESK) channel results in nonfunctional channels. Moreover, mutant TRESK subunits exert a dominant-negative effect on whole cell TRESK currents and result in hyperexcitability of small-diameter trigeminal ganglion (TG) neurons, suggesting that mutant TRESK may increase the gain of the neuronal circuit underlying migraine headache. However, the nonmigraine-associated TRESK C110R variant exhibits the same effect on TRESK currents as the mutant subunits in Xenopus oocytes, suggesting that dysfunction of TRESK is not sufficient to cause migraine. Here, we confirmed that the C110R variant formed nonfunctional channels and exerted a dominant-negative effect on TRESK currents in HEK293T cells, similar to the migraine-associated mutant TRESK. To compare the functional consequences of TRESK mutations/variants in a more physiological setting, we expressed the mutant TRESK and the C110R variant in cultured mouse TG neurons and investigated their effects on background K ϩ currents and neuronal excitability. Both mutant TRESK and the C110R variant reduced the endogenous TRESK currents in TG neurons, but the effect of the C110R variant was significantly smaller. Importantly, only TG neurons expressing mutant TRESK subunits, but not those expressing the C110R variant, exhibited a significant increase in excitability. Thus only the migraine-associated TRESK mutation, but not the C110R variant, reduces the endogenous TRESK currents to a degree that affects TG excitability. Our results support a potential causal relationship between the frameshift TRESK mutation and migraine susceptibility.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nonmigraine-associated TRESK K⁺ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

Guo

Liu

Ren

et al. 2014

Journal of Neurophysiology

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“…While activation of P2X3 receptors in TG neurons increases neuronal excitability (Hullugundi et al . ), this study suggests that the ensuing spike activity could evoke ATP release independent from CaMKII, as demonstrated by lack of KN‐93 inhibition. Nevertheless, CaMKII‐dependent ATP release was readily evident with the broad depolarization evoked by high K + .…”

Section: Discussionmentioning

confidence: 56%

“…A model for functional implications of the CASK/Panx1/ P2X3 receptor complex ATP is co-released with other neurotransmitters (Jo and Schlichter 1999;Nakatsuka and Gu 2001) and ATP-sensing P2X3 receptors are expressed at the pre-synaptic level (Burnstock 2006), where they are thought to have a modulatory role on neurotransmission (Gu and MacDermott 1997;Aoyama et al 2011). While activation of P2X3 receptors in TG neurons increases neuronal excitability (Hullugundi et al 2014), this study suggests that the ensuing spike activity could evoke ATP release independent from CaMKII, as demonstrated by lack of KN-93 inhibition. Nevertheless, CaMKII-dependent ATP release was readily evident with the broad depolarization evoked by high K + .…”

Section: Discussionmentioning

confidence: 99%

The scaffold protein calcium/calmodulin‐dependent serine protein kinase controls ATP release in sensory ganglia upon P2X3 receptor activation and is part of an ATP keeper complex

Bele

Fabbretti

2016

Journal of Neurochemistry

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P2X3 receptors, gated by extracellular ATP, are expressed by sensory neurons and are involved in peripheral nociception and pain sensitization. The ability of P2X3 receptors to transduce extracellular stimuli into neuronal signals critically depends on the dynamic molecular partnership with the calcium/calmodulin-dependent serine protein kinase (CASK). The present work used trigeminal sensory neurons to study the impact that activation of P2X3 receptors (evoked by the agonist a,b-meATP) has on the release of endogenous ATP and how CASK modulates this phenomenon. P2X3 receptor function was followed by ATP efflux via Pannexin1 (Panx1) hemichannels, a mechanism that was blocked by the P2X3 receptor antagonist A-317491, and by P2X3 silencing. ATP efflux was enhanced by nerve growth factor, a treatment known to potentiate P2X3 receptor function. Basal ATP efflux was not controlled by CASK, and carbenoxolone or Pannexin silencing reduced ATP release upon P2X3 receptor function. CASK-controlled ATP efflux followed P2X3 receptor activity, but not depolarization-evoked ATP release. Molecular biology experiments showed that CASK was essential for the transactivation of Panx1 upon P2X3 receptor activation. These data suggest that P2X3 receptor function controls a new type of feed-forward purinergic signaling on surrounding cells, with consequences at peripheral and spinal cord level. Thus, P2X3 receptor-mediated ATP efflux may be considered for the future development of pharmacological strategies aimed at containing neuronal sensitization.

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“…It has also been reported that silencing C-terminal Src inhibitory kinase in TG neurons potentiated P2X3R responses, thus identifying another potential target for TG pain suppression [24]. Moreover, P2X3R activity on mouse TG sensory neurons was enhanced by the familial hemiplegic migraine type 1 (FHM-1) calcium channel mutation R192Q [25]; in fact, TG sensory neurons from FHM-1 knock-in mice exhibited a lower firing threshold and generated more action potentials in response to α,β-meATP, acting via P2X3Rs [26]. Therefore, the P2X3R pathway represents a promising candidate for the development of innovative antimigraine drug.…”

Section: P2x Ion-channel Receptors and Chronic Painmentioning

confidence: 99%

Tackling Chronic Pain and Inflammation through the Purinergic System

Magni

Riccio

Ceruti

2018

CMC

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The purinergic system is composed of purine and pyrimidine transmitters, of the enzymes that modulate the interconversion of nucleotides and nucleosides, of the membrane transporters that control their extracellular concentrations, and of the many receptor subtypes that are responsible for their cellular responses. The components of this system are ubiquitously localized in all tissues and organs, and their involvement in several physiological conditions has been clearly demonstrated. Moreover, extracellular purine and pyrimidine concentrations raise several folds under pathological conditions like tissue damage, ischemia, and inflammation, which suggest that this signaling system might contribute both to disease outcome and, possibly, to its tentative resolution. The complexity of this system has greatly impaired the clear identification of the mediators and receptors that are actually involved in a given pathology, also due to the often opposite roles played by the various receptor subtypes. Nevertheless, this knowledge is fundamental for the possible exploitation of these molecular entities as targets for the development of new pharmacological approaches. In this review, we aim at highlighting what is currently known on the role of the purinergic system in various pain conditions and during inflammatory processes. Although some confusion may arise from conflicting 2 results, literature data clearly show that targeting specific purinergic receptors may represent an innovative approach to various pain and inflammatory conditions, and that new purine-based drugs are now very close to reach the market with these indications.

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A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1

Cited by 25 publications

References 45 publications

Nonmigraine-associated TRESK K⁺ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

Nonmigraine-associated TRESK K⁺ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

The scaffold protein calcium/calmodulin‐dependent serine protein kinase controls ATP release in sensory ganglia upon P2X3 receptor activation and is part of an ATP keeper complex

Tackling Chronic Pain and Inflammation through the Purinergic System

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A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1

Cited by 25 publications

References 45 publications

Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

The scaffold protein calcium/calmodulin‐dependent serine protein kinase controls ATP release in sensory ganglia upon P2X3 receptor activation and is part of an ATP keeper complex

Tackling Chronic Pain and Inflammation through the Purinergic System

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Product

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Nonmigraine-associated TRESK K⁺ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

Nonmigraine-associated TRESK K⁺ channel variant C110R does not increase the excitability of trigeminal ganglion neurons