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Pain
2017 Nov 01;15811:2155-2168. doi: 10.1097/j.pain.0000000000001021.
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Cyclin-dependent kinase 5 modulates the P2X2a receptor channel gating through phosphorylation of C-terminal threonine 372.
Coddou C
,
Sandoval R
,
Castro P
,
Lazcano P
,
Hevia MJ
,
Rokic M
,
Hall B
,
Terse A
,
Gonzalez-Billault C
,
Kulkarni AB
,
Stojilkovic SS
,
Utreras E
.
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The purinergic P2X2 receptor (P2X2R) is an adenosine triphosphate-gated ion channel widely expressed in the nervous system. Here, we identified a putative cyclin-dependent kinase 5 (Cdk5) phosphorylation site in the full-size variant P2X2aR (TPKH), which is absent in the splice variant P2X2bR. We therefore investigated the effects of Cdk5 and its neuronal activator, p35, on P2X2aR function. We found an interaction between P2X2aR and Cdk5/p35 by co-immunofluorescence and co-immunoprecipitation in HEK293 cells. We also found that threonine phosphorylation was significantly increased in HEK293 cells co-expressing P2X2aR and p35 as compared to cells expressing only P2X2aR. Moreover, P2X2aR-derived peptides encompassing the Cdk5 consensus motif were phosphorylated by Cdk5/p35. Whole-cell patch-clamp recordings indicated a delay in development of use-dependent desensitization (UDD) of P2X2aR but not of P2X2bR in HEK293 cells co-expressing P2X2aR and p35. In Xenopus oocytes, P2X2aRs showed a slower UDD than in HEK293 cells and Cdk5 activation prevented this effect. A similar effect was found in P2X2a/3R heteromeric currents in HEK293 cells. The P2X2aR-T372A mutant was resistant to UDD. In endogenous cells, we observed similar distribution between P2X2R and Cdk5/p35 by co-localization using immunofluorescence in primary culture of nociceptive neurons. Moreover, co-immunoprecipitation experiments showed an interaction between Cdk5 and P2X2R in mouse trigeminal ganglia. Finally, endogenous P2X2aR-mediated currents in PC12 cells and P2X2/3R mediated increases of intracellular Ca in trigeminal neurons were Cdk5 dependent, since inhibition with roscovitine accelerated the desensitization kinetics of these responses. These results indicate that the P2X2aR is a novel target for Cdk5-mediated phosphorylation, which might play important physiological roles including pain signaling.
Ase,
Potentiation of P2X1 ATP-gated currents by 5-hydroxytryptamine 2A receptors involves diacylglycerol-dependent kinases and intracellular calcium.
2005, Pubmed,
Xenbase
Ase,
Potentiation of P2X1 ATP-gated currents by 5-hydroxytryptamine 2A receptors involves diacylglycerol-dependent kinases and intracellular calcium.
2005,
Pubmed
,
Xenbase
Bórquez,
Bioinformatic survey for new physiological substrates of Cyclin-dependent kinase 5.
2013,
Pubmed
Boué-Grabot,
A protein kinase C site highly conserved in P2X subunits controls the desensitization kinetics of P2X(2) ATP-gated channels.
2000,
Pubmed
,
Xenbase
Brake,
New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor.
1994,
Pubmed
,
Xenbase
Brändle,
Desensitization of the P2X(2) receptor controlled by alternative splicing.
1997,
Pubmed
,
Xenbase
Brown,
Protein kinase A regulation of P2X(4) receptors: requirement for a specific motif in the C-terminus.
2010,
Pubmed
Burnstock,
Purinergic mechanosensory transduction and visceral pain.
2009,
Pubmed
Burnstock,
Purinergic Mechanisms and Pain.
2016,
Pubmed
Burnstock,
Physiology and pathophysiology of purinergic neurotransmission.
2007,
Pubmed
Cerda,
Mining recent brain proteomic databases for ion channel phosphosite nuggets.
2011,
Pubmed
Chen,
CaMKIIα and caveolin-1 cooperate to drive ATP-induced membrane delivery of the P2X3 receptor.
2014,
Pubmed
Chow,
Functional modulation of P2X2 receptors by cyclic AMP-dependent protein kinase.
1998,
Pubmed
Clyne,
The role of histidine residues in modulation of the rat P2X(2) purinoceptor by zinc and pH.
2002,
Pubmed
,
Xenbase
Coddou,
Activation and regulation of purinergic P2X receptor channels.
2011,
Pubmed
Coddou,
Reactive oxygen species potentiate the P2X2 receptor activity through intracellular Cys430.
2009,
Pubmed
,
Xenbase
Coddou,
Role of domain calcium in purinergic P2X2 receptor channel desensitization.
2015,
Pubmed
D'Arco,
The C-terminal Src inhibitory kinase (Csk)-mediated tyrosine phosphorylation is a novel molecular mechanism to limit P2X3 receptor function in mouse sensory neurons.
2009,
Pubmed
De Roo,
Selective potentiation of homomeric P2X2 ionotropic ATP receptors by a fast non-genomic action of progesterone.
2010,
Pubmed
,
Xenbase
Dhariwala,
An unusual member of the Cdk family: Cdk5.
2008,
Pubmed
Dhavan,
A decade of CDK5.
2001,
Pubmed
Fang-Hu,
Cdk5 contributes to inflammation-induced thermal hyperalgesia mediated by the p38 MAPK pathway in microglia.
2015,
Pubmed
Fujiwara,
Regulation of the desensitization and ion selectivity of ATP-gated P2X2 channels by phosphoinositides.
2006,
Pubmed
,
Xenbase
Harada,
ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1.
2001,
Pubmed
Hawasli,
Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation.
2007,
Pubmed
Jendryke,
TRPV1 function is modulated by Cdk5-mediated phosphorylation: insights into the molecular mechanism of nociception.
2016,
Pubmed
Jiang,
Subunit arrangement in P2X receptors.
2003,
Pubmed
Khadra,
Gating properties of the P2X2a and P2X2b receptor channels: experiments and mathematical modeling.
2012,
Pubmed
Koshimizu,
Identification of amino acid residues contributing to desensitization of the P2X2 receptor channel.
1998,
Pubmed
Kowalski,
Flexible subunit stoichiometry of functional human P2X2/3 heteromeric receptors.
2015,
Pubmed
,
Xenbase
Lew,
A brain-specific activator of cyclin-dependent kinase 5.
1994,
Pubmed
Lewis,
Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons.
1995,
Pubmed
Li,
Regulation of NMDA receptors by cyclin-dependent kinase-5.
2001,
Pubmed
Liu,
Phosphorylation of TRPV1 by cyclin-dependent kinase 5 promotes TRPV1 surface localization, leading to inflammatory thermal hyperalgesia.
2015,
Pubmed
Lorca,
Extracellular histidine residues identify common structural determinants in the copper/zinc P2X2 receptor modulation.
2005,
Pubmed
,
Xenbase
Mohapatra,
Regulation of Ca2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase.
2005,
Pubmed
Mohapatra,
Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway.
2003,
Pubmed
Moss,
Modulation of amino acid-gated ion channels by protein phosphorylation.
1996,
Pubmed
Nair,
The Cdk5 kinase downregulates ATP-gated ionotropic P2X3 receptor function via serine phosphorylation.
2010,
Pubmed
Newbolt,
Membrane topology of an ATP-gated ion channel (P2X receptor).
1998,
Pubmed
,
Xenbase
Pareek,
Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1.
2007,
Pubmed
Pareek,
Cdk5: a new player in pain signaling.
2006,
Pubmed
Park,
Graded regulation of the Kv2.1 potassium channel by variable phosphorylation.
2006,
Pubmed
Paukert,
Inflammatory mediators potentiate ATP-gated channels through the P2X(3) subunit.
2001,
Pubmed
,
Xenbase
Peng,
Colon mustard oil instillation induced cross-organ reflex sensitization on the pelvic-urethra reflex activity in rats.
2009,
Pubmed
Pingle,
Capsaicin receptor: TRPV1 a promiscuous TRP channel.
2007,
Pubmed
Prochazkova,
Activation of cyclin-dependent kinase 5 mediates orofacial mechanical hyperalgesia.
2013,
Pubmed
Rozas,
Targeted overexpression of tumor necrosis factor-α increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons.
2016,
Pubmed
Simon,
Localization and functional expression of splice variants of the P2X2 receptor.
1997,
Pubmed
,
Xenbase
Surprenant,
Signaling at purinergic P2X receptors.
2009,
Pubmed
Swope,
Regulation of ligand-gated ion channels by protein phosphorylation.
1999,
Pubmed
Tomizawa,
Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity.
2002,
Pubmed
Utreras,
Transforming growth factor-β1 regulates Cdk5 activity in primary sensory neurons.
2012,
Pubmed
Utreras,
Cyclin-dependent kinase 5 activator p35 over-expression and amyloid beta synergism increase apoptosis in cultured neuronal cells.
2009,
Pubmed
Utreras,
Tumor necrosis factor-alpha regulates cyclin-dependent kinase 5 activity during pain signaling through transcriptional activation of p35.
2009,
Pubmed
Utreras,
Resveratrol inhibits Cdk5 activity through regulation of p35 expression.
2011,
Pubmed
Utreras,
TGF-β1 sensitizes TRPV1 through Cdk5 signaling in odontoblast-like cells.
2013,
Pubmed
Utreras,
Molecular Roles of Cdk5 in Pain Signaling.
2009,
Pubmed
Vissel,
A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux.
2001,
Pubmed
Wang,
A critical role of the cAMP sensor Epac in switching protein kinase signalling in prostaglandin E2-induced potentiation of P2X3 receptor currents in inflamed rats.
2007,
Pubmed
Wang,
Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety.
2015,
Pubmed
Xing,
Cyclin-dependent kinase 5 controls TRPV1 membrane trafficking and the heat sensitivity of nociceptors through KIF13B.
2012,
Pubmed
