ライフサイエンスコーパス: kainate receptor

1 nd-binding domain of a light-gated mammalian kainate receptor.

2 1 prevents kainate-evoked endocytosis of the kainate receptor.

3 xcitability through their actions on AMPA or kainate receptors.

4 roxy-5-methyl-4-isoxazolepropionic acid] and kainate receptors.

5 ontaining NMDA receptors as well as AMPA and kainate receptors.

6 combinant homomeric and heteromeric AMPA and kainate receptors.

7 discharges in BLA slices in vitro via GluK1 kainate receptors.

8 rgic ACs do not appear to express functional kainate receptors.

9 e involvement of Ca(2+)/calcineurin and AMPA/kainate receptors.

10 ties by having subnanomolar IC(50) values at kainate receptors.

11 st that Neto2 modulates the function of most kainate receptors.

12 tion, desensitization, and ion modulation in kainate receptors.

13 ferent from those of the homologous AMPA and kainate receptors.

14 es that contained GluK1, GluK1/5, or GluK2/5 kainate receptors.

15 ivity for effectively blocking both AMPA and kainate receptors.

16 c currents in neurons expressing recombinant kainate receptors.

17 for recombinant NMDA receptors over AMPA and kainate receptors.

18 s that can potentially inhibit both AMPA and kainate receptors.

19 tion of inhibitory presynaptic terminals via kainate receptors.

20 oxicity, mediated through activation of AMPA/kainate receptors.

21 n the activation properties of the remaining kainate receptors.

22 m that resembles desensitization at AMPA and kainate receptors.

23 or sodium in order for glutamate to activate kainate receptors.

24 r dissection of ligand binding and gating in kainate receptors.

25 positive for mGluR5 and GLU(K5-7)-containing kainate receptors.

26 luR3 for AMPA, and KA2>GluR5>GluR7>GluR6 for kainate receptors.

27 y selective antagonist of GLU(K5)-containing kainate receptors.

28 ions are essential structural components of kainate receptors.

29 chemic axonal injury is not mediated by AMPA/kainate receptors.

30 , ischemic axonal damage is mediated by AMPA/kainate receptors.

31 tly the activity of both the GluK1 and GluK2 kainate receptors.

32 on structure currently exists of heteromeric kainate receptors.

33 hyl-4-isoxazolepropionic acid receptors, and kainate receptors.

34 rter version (55 nt) inhibited both AMPA and kainate receptors.

35 F bipolar cells were exclusively mediated by kainate receptors.

36 -hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors.

37 e granule cells and operate via postsynaptic kainate receptors.

38 found in all vertebrate NMDA but not AMPA or kainate receptors.

39 AMPA/kainate receptor activation alone elicited calcium signa

40 Combined NMDA and AMPA/kainate receptor activation elicited calcium signals in

41 We therefore investigated the effects of kainate receptor activation on GABA release in rat prefr

42 ggest that the balance between NMDA and AMPA/kainate receptor activation regulates the axonal arboriz

43 ed antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability

44 in GluK5 expression is sufficient to enhance kainate receptor activity by modulating receptor channel

45 at loss of synaptic AMPA receptors increased kainate receptor activity in cerebellar granule cells wi

46 acological inhibition or genetic ablation of kainate receptor activity reduces pain behaviors in a nu

47 e demonstrate that the desensitized state of kainate receptors acts as a deep energy well offsetting

48 as occurs in all previously solved AMPA and kainate receptor agonist and antagonist complexes.

49 nals at synapses that contain either AMPA or kainate receptors, all with different temporal propertie

50 ed EPSCs, whether they were mediated by AMPA/kainate receptors alone or in combination with NMDA rece

51 AMPA and kainate receptors, along with NMDA receptors, represent

52 ochemistry, and pharmacology to identify the kainate receptor and auxiliary subunits in ground squirr

53 lation of GluR6 regulates endocytosis of the kainate receptor and modifies synaptic transmission.

54 ; a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) tha

55 he agonist-bound state that are conserved in kainate receptors and absent in AMPA receptors.

56 pathway requires the metabotropic action of kainate receptors and activation of G protein, protein k

57 ke-2 (Neto2) as a novel accessory subunit of kainate receptors and showed that Neto2 modulates the ga

58 d pentylenetetrazol is not mediated by GluK1 kainate receptors, and deletion of these receptors does

59 The AMPA/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulf

60 The AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2

61 on treatment of an acutely administered AMPA/kainate receptor antagonist and delayed transplantation

62 These findings show that a highly selective kainate receptor antagonist can affect the deficits in s

63 These data suggest that an AMPA/kainate receptor antagonist can represent a novel therap

64 no-3-hydroxy-5-methyl-4-isoxazole propionate/kainate receptor antagonist CNQX (0, .01, .03, .1 mug/si

65 sent experiments, administration of the AMPA/kainate receptor antagonist CNQX (0, 0.03, or 0.3 mug) i

66 finding that intracore injection of the AMPA/kainate receptor antagonist CNQX attenuated the ability

67 NMDAR antagonist MK801, and also by the AMPA/kainate receptor antagonist CNQX.

68 The AMPA/kainate receptor antagonist NBQX was directly administer

69 havioral responses to kainic acid and that a kainate receptor antagonist normalized altered behaviors

70 We found that UBP-310, a kainate receptor antagonist with high selectivity for Gl

71 t work examined effects of another selective kainate receptor antagonist, (S)-1-(2-Amino-2-carboxyeth

72 A) receptor antagonist, but not an NMDA/AMPA/kainate receptor antagonist, suggesting that they were m

73 further support for the idea that selective kainate receptor antagonists could be novel therapeutic

74 These findings suggest that selective kainate receptor antagonists could be novel therapeutic

75 Compounds 18i and (-)-4 were the most potent kainate receptor antagonists, and 18i was selective for

76 l-4-isoxazolepropionic acid, and heteromeric kainate receptors are all downstream targets of GPCR sig

77 Kainate receptors are also expressed throughout central

78 Kainate receptors are further classified into low-affini

79 Kainate receptors are glutamate-gated cation-selective c

80 AMPA and kainate receptors are glutamate-gated ion channels whose

81 Recombinant kainate receptors are inhibited in a subunit-dependent m

82 Kainate receptors are less well understood than other gl

83 n performed on homomeric GluK2 but, in vivo, kainate receptors are likely heterotetramers.

84 uK2 knock-out mice, demonstrating that GluK1 kainate receptors are not required for epileptogenesis o

85 Kainate receptors are widely expressed in the brain, and

86 AMPA/kainate receptors as well as metabotropic glutamate rece

87 g the different temporal signalling roles of kainate receptors, as cones release glutamate over a ran

88 ptically released zinc inhibits postsynaptic kainate receptors at mossy fiber synapses and limits fre

89 properties and kinetic behaviour of AMPA and kainate receptors at the level of single receptor molecu

90 of glutamate receptors (i.e. AMPA, NMDA, and kainate receptors) at the synapse.

91 ntly solved crystal structures for the GluK2 kainate receptor ATD as a guide, we performed cysteine m

92 The association of kainate receptor ATD dimers is generally weaker than the

93 The free energy maps of AMPA and kainate receptor ATD dimers provide a framework for the

94 AMPA/kainate receptor blockade (NBQX, 100 microM) or Group II

95 al/pharmacological data showed that CeA AMPA/kainate receptor blockade attenuates cisplatin-induced p

96 n trained rabbits was injected with the AMPA/kainate receptor blocker, 1,2,3,4-tetrahydro-6-nitro-2,3

97 -5-methylisoxazol-4-yl)propanoate (AMPA) and kainate receptors bound to full and partial agonists.

98 bipolar cells was blocked by antagonists to kainate receptors but not AMPA receptors.

99 -methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, but only oscillations in the DP were

100 Strikingly, the activation of kainate receptors by glutamate requires the presence of

101 e presence of zinc, a fall in pH potentiates kainate receptors by relieving zinc inhibition.

102 In neurons, kainate receptors can associate with the auxiliary subun

103 In contrast, desensitization of kainate receptors can be slowed, but not blocked, by sim

104 Kainate receptors can be subject to voltage-dependent bl

105 While some AMPA and kainate receptors can form functional homomeric ion chan

106 systemic ATPA, acting specifically via GluK1 kainate receptors, causes locomotor arrest and forelimb

107 d knockdown, we determine that Tm5c uses the kainate receptor Clumsy to receive excitatory glutamate

108 just through the NMDA but also mGlu and AMPA/Kainate receptors, completely reversed the cell death ph

109 However, many AMPA and kainate receptor complexes in vivo are heteromers compos

110 ycosylation and cell surface localization of kainate receptors composed of GluK2/3 subunits.

111 tropic glutamate receptor 7) and GluK2-KARs (kainate receptors containing glutamate receptor, ionotro

112 We conclude that selective activation of kainate receptors containing the GluK1 subunit can trigg

113 Kainate receptors containing the GluK1 subunit have an i

114 Kainate receptors contribute to synaptic plasticity and

115 Although annotated as glutamate and kainate receptors, crystal structures of the ML032222a a

116 tly as auxiliary proteins that slowed GluK2a kainate receptor current kinetics without impacting rece

117 ulted in a significant reduction in synaptic kainate receptor currents.

118 ) a dorsomedial region characterized by high kainate receptor density.

119 Like classical LTP, kainate-receptor-dependent LTP recruits recycling endoso

120 isulfides has been previously shown to block kainate receptor desensitization completely.

121 show that sodium and chloride ions modulate kainate receptor dimer affinity as much as 50-fold, and

122 tor mutants and directly measured changes in kainate receptor dimer stability by analytical ultracent

123 the energetic effects of allosteric ions on kainate receptor dimer stability in solution, using a Gl

124 than other glutamate receptors, and synaptic kainate receptors display properties that differ from re

125 r, heterologous expression of the Drosophila kainate receptor DKaiR1D and the AMPA receptor DGluR1A r

126 ptic Ca(2+) influx through calcium-permeable kainate receptors during its induction.

127 Kainate receptors exhibit a highly compartmentalized dis

128 tective effect is mediated through increased kainate receptor expression.

129 ropic receptor with metabotropic properties (kainate receptors) failed to prevent depolarization-indu

130 However, the kainate receptor family consists of five different subun

131 The kainate receptor family of glutamate-gated ion channels

132 selectivity among the more distantly related kainate receptor family.

133 us the plasma membrane localization of GluR6 kainate receptors following mutagenesis of the LBD.

134 aturated in CSF, and that the requirement of kainate receptors for Na(+) occurs simply because other

135 nglion cells confirmed the essential role of kainate receptors for signaling in both transient and su

136 or the high-affinity subunits for ionotropic kainate receptor function and further demonstrate that k

137 new roles for Neto1 and Neto2 in regulating kainate receptor function and identify domains within th

138 This review will cover kainate receptor function and participation in pain sign

139 ould underlie some of the unusual aspects of kainate receptor function in the mammalian CNS.

140 for the PKC-dependent regulation of synaptic kainate receptor function observed during various forms

141 caused complete loss of synaptic ionotropic kainate receptor function.

142 a potentially useful new tool for dissecting kainate receptor function.

143 densities for glutamatergic AMPA, NMDA, and kainate receptors; GABAA receptors; muscarinic M1 , M2 a

144 sitizing D776K mutant provides insights into kainate receptor gating and represents a potentially use

145 Here, by determining the structure of the kainate receptor GluK2 subtype in its desensitized state

146 expression are decreased in mice lacking the kainate receptor GluR6.

147 entified some known SAP102 binding partners, kainate receptor GluR6/7 and inward rectifier potassium

148 n of Neto subunits with recombinant GluK2(Q) kainate receptors greatly reduced inward rectification w

149 Delineating the roles of kainate receptors has been hampered by sub-optimal pharm

150 good evidence that both heteromeric AMPA and kainate receptors have a 2:2 subunit stoichiometry and a

151 Kainate receptor heteromerization and auxiliary subunits

152 he present study highlights the role of AMPA-kainate receptor in IVH-induced white matter injury and

153 the desensitization properties of the GluR6 kainate receptor in response to glutamate application, a

154 pharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramate's effect

155 sed 4.1N interaction with GluK2/3-containing kainate receptors in acute brain slices, an effect that

156 d with combined activation of muscarinic and kainate receptors in different subregions of the medial

157 Neuronal kainate receptors in dorsal root ganglia were sensitive

158 The presence of GluK2 kainate receptors in L2/3 enhances synaptic transmission

159 roblasts express mGluR5 and Ca(2+)-permeable kainate receptors in mouse slices.

160 uously released in darkness, activating AMPA/kainate receptors in postsynaptic neurons.

161 eceptor subunits to assess the role of GluK1 kainate receptors in provoking seizures and in kindling

162 We investigated the role of kainate receptors in the generation of theta oscillation

163 previously unsuspected role for postsynaptic kainate receptors in the induction of functional and str

164 y, it was reported that inactivation of AMPA/kainate receptors in the IO produces extinction of condi

165 ceptors was mediated exclusively through the kainate receptors in the transient OFF bipolar cells, wh

166 onotropic glutamate receptors, including the kainate receptor, in the central nervous system.

167 ical studies demonstrated that activation of kainate receptors increased the frequency, but not the a

168 AMPA-kainate receptor induced excitotoxicity contributes to o

169 Our data suggest that AMPA-kainate receptor inhibition alleviates OPC loss and IVH-

170 Here, we show that AMPA-kainate receptor inhibition by NBQX suppresses inflammat

171 via AMPA receptor activation, and that AMPA-kainate receptor inhibition suppresses inflammation and

172 ntagonists of these receptors, especially of kainate receptors, is useful for developing potential tr

173 selectivity toward native GLU(K5)-containing kainate receptors (K(D) 0.105 +/- 0.007 microM vs kainat

174 Here, we show that kainate receptor (KAR) heteromerization and association

175 Phosphorylation or SUMOylation of the kainate receptor (KAR) subunit GluK2 have both individua

176 ole(s) of Rab17 in AMPA receptor (AMPAR) and kainate receptor (KAR) trafficking.

177 Neto) 1 and Neto2, the auxiliary subunits of kainate receptor (KARs), are phosphorylated by multiple

178 Kainate receptors (KARs) are a subfamily of ionotropic g

179 Kainate receptors (KARs) are found ubiquitously in the C

180 Kainate receptors (KARs) are important modulators of syn

181 Kainate receptors (KARs) are involved in the modulation

182 Kainate receptors (KARs) are ionotropic glutamate ion ch

183 Kainate receptors (KARs) are ionotropic glutamate recept

184 Kainate receptors (KARs) are ionotropic glutamate recept

185 Kainate receptors (KARs) are neuronal proteins that exhi

186 mit high temporal frequency signals, whereas kainate receptors (KARs) are presumed to encode lower te

187 Heteromeric kainate receptors (KARs) can be assembled from varying c

188 Here we show that activation of kainate receptors (KARs) causes GlyR endocytosis in a ca

189 Kainate receptors (KARs) consist of a class of ionotropi

190 Kainate receptors (KARs) contribute to postsynaptic exci

191 Presynaptic kainate receptors (KARs) exert a modulatory action on tr

192 Activation of presynaptic kainate receptors (KARs) has been shown to reduce inhibi

193 e classes of ionotropic glutamate receptors, kainate receptors (KARs) have a unique brain distributio

194 Kainate receptors (KARs) have been implicated in a numbe

195 Interneuronal kainate receptors (KARs) regulate GABAergic transmission

196 coassemble with NMDA receptors (NMDARs) and kainate receptors (KARs) to modulate their function.

197 Kainate receptors (KARs), a family of ionotropic glutama

198 ons of the dorsal root ganglia (DRG) express kainate receptors (KARs), a subfamily of glutamate recep

199 urons in the neonatal DRG express functional kainate receptors (KARs), one of three subfamilies of io

200 NETO1 and NETO2 are auxiliary subunits of kainate receptors (KARs).

201 , little is known about the effect of ACh on kainate receptors (KARs).

202 lutamate receptors (mGluRs) and augmented by kainate receptors (KARs).

203 nabling efficient 2P activation of the GluK2 kainate receptor, LiGluR.

204 Postsynaptic kainate receptors mediate excitatory synaptic transmissi

205 AMPA and kainate receptors mediate fast synaptic transmission.

206 Kainate receptors mediate fast, excitatory synaptic tran

207 c glutamate receptors (iGluRs), the NMDA and kainate receptors, mediate a majority of excitatory neur

208 Kainate receptors mediated approximately 80% of the syna

209 Kainate receptors mediated responses to contrast modulat

210 Although the kainate receptors mediated the light responses in the su

211 ne or PKA with either H89 or RpcAMPs blocked kainate receptor-mediated actions but did not prevent th

212 cologically isolated NMDA receptor- and AMPA/kainate receptor-mediated components of the fully develo

213 The augmentation of kainate receptor-mediated currents in the absence of AMP

214 CT depolarisation evoked short-latency, AMPA/kainate receptor-mediated EPSCs in connected GCL neurons

215 ction of both NMDA receptor (NMDAR) and AMPA/kainate receptor-mediated evoked excitatory postsynaptic

216 Both cell types receive predominantly AMPA/kainate receptor-mediated excitatory synaptic input that

217 Despite this, kainate receptor-mediated inhibition of the slow afterhy

218 e activity of MSNs via a glutamatergic, AMPA/kainate receptor-mediated mechanism, indicated by increa

219 dings in hippocampal slices demonstrate that kainate-receptor-mediated excitatory postsynaptic curren

220 fficking of the receptors and also modulates kainate-receptor-mediated mEPSCs.

221 gate this, we constructed a library of GluR6 kainate receptor mutants and directly measured changes i

222 tive activity, may therefore serve to unmask kainate receptor neurotransmission.

223 Relative to the homologous AMPA and kainate receptors, NMDA receptors have additional inters

224 normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses.

225 The kainate receptor occupies a position distinct from that

226 Kainate receptors of astrocytes act as sensors of extrac

227 Within individual neurons, kainate receptors of different subunit compositions are

228 identified glutamate receptors, for example, kainate receptors on which NMDA acts as a competitive an

229 NMDAR antagonists, but not blockers of AMPA/kainate receptors or voltage-gated sodium channels, prev

230 ceptor function and further demonstrate that kainate receptor participation in metabotropic signaling

231 NMDA receptors and kainate receptors play roles in synaptic transmission, b

232 ndly slows the desensitization rate of GluK1 kainate receptors, promotes plasma membrane localization

233 receptor; GluR5-7 and KA1-2 subunits of the kainate receptor; PSD95), all but two (GluR4 and KA1) we

234 utive mGluR7 recruitment and regulated GluK2 kainate receptor recruitment, revealing a mechanism that

235 r results have revealed a mechanism by which kainate receptors regulate KCC2 expression in the hippoc

236 Furthermore, we found that kainate receptors regulate the surface expression of NET

237 Kainate receptors require the presence of external ions

238 relate of this action - activation of PKC by kainate receptors - requires G alpha(i/o) proteins.

239 erface mutants, and that the deactivation of kainate receptor responses is dominated by entry into de

240 Kainate receptor responses to domoate are characterized

241 receptor, along with the wild-type rat GluK2 kainate receptor (rGluK2) as the control.

242 We conclude that zinc modulation of kainate receptors serves an important role in shaping ka

243 AMPA and kainate receptors share a high degree of sequence and st

244 The 7.6 A structure of a desensitized kainate receptor shows how these changes accommodate cha

245 hly with expression of Ca(2+)-permeable AMPA/kainate receptors, shows a laminar pattern of distributi

246 Kainate receptors signal through both ionotropic and met

247 Incorporation of NETO proteins into kainate receptor-signaling complexes therefore extends t

248 oxy-5-methyl-4-isoxazole propionic acid) and kainate receptor subtypes in their major functional stat

249 resting and desensitized states of AMPA and kainate receptor subtypes, the ion channels are closed,

250 ubunits that combined segments from NMDA and kainate receptors, subtypes with distinct pharmacologica

251 of a single gene coding for a high-affinity kainate receptor subunit (i.e., grik4) in a limited area

252 g that fusing the N-terminal 150 residues of kainate receptor subunit 2 (KA2) to the recently discove

253 The grik2 gene, coding for the kainate receptor subunit GluK2 (formerly GluR6), is asso

254 hippocampal neurons, we discovered that the kainate receptor subunit GluK2 and the auxiliary subunit

255 loop apex and the transmembrane M3 helix of kainate receptor subunit GluK2.

256 -I mRNA editing at the Q/R site of the human kainate receptor subunit GluR5 and was compared with two

257 d the splicing pattern and expression of the kainate receptor subunit GluR6 in human fibroblast cell

258 are present at synapses and we show that the kainate receptor subunit GluR6 is a SUMO substrate.

259 We conclude that GluK1 is the predominant kainate receptor subunit in cb1 and cb3 Off bipolar cell

260 as a critical mechanism for retention of the kainate receptor subunit KA2 in the endoplasmic reticulu

261 GluK2 is a kainate receptor subunit that is alternatively spliced a

262 wn about the molecular mechanisms regulating kainate receptor subunit trafficking.

263 The results show that NETO2 is a kainate receptor subunit with significant effects on glu

264 reased expression of the GluK5 high-affinity kainate receptor subunit.

265 sphorylation in the trafficking of the GluR6 kainate receptor subunit.

266 with homologous segments from the rat GluK2 kainate receptor subunit.

267 -expression of Neto1 and 2 with pore-forming kainate receptor subunits also increases the duration of

268 Kainate receptor subunits can form functional channels a

269 Here we report that the GluK1 and GluK2 kainate receptor subunits interact with the spectrin-act

270 ction with mice deficient in GluK1 and GluK2 kainate receptor subunits to assess the role of GluK1 ka

271 FB9s-b selectively inhibited GluK1 and GluK2 kainate receptor subunits, and also GluK1/GluK5 and GluK

272 ans in the disease state, including AMPA and kainate receptor subunits, glutamate transporters EAAT1

273 Xenopus oocytes injected with cRNA encoding kainate receptor subunits, we have observed that heterom

274 In particular, the slow decay of kainate receptor synaptic currents contrasts with the ra

275 ained 25 genes involved in the regulation of kainate receptors, TGF-beta and Wnt signaling, as well a

276 1a/b cells were mediated by GluK1-containing kainate receptors that behaved differently from the rece

277 much less well understood, particularly for kainate receptors that exist as multiple subtypes with a

278 id (ATPA), a potent and selective agonist of kainate receptors that include the GluK1 subunit, in con

279 ty and by synaptic activation of presynaptic kainate receptors that increase release probability on s

280 xcitatory neurotransmitter that binds to the kainate receptor, the N-methyl-D-aspartate (NMDA) recept

281 could be related to increased sensitivity of kainate receptors to endogenous glutamate, effects of th

282 However, allocation of functional kainate receptors to known cell types and their sensitiv

283 mately 21 A resolution, of full-length GluK2 kainate receptors trapped in antagonist-bound resting an

284 at an aberrant readout of synaptic inputs by kainate receptors triggered a long-lasting impairment of

285 Similarly, the most common phenotype for kainate receptor variants is intellectual disability.

286 erologous systems, the temporal responses of kainate receptors vary when different channel-forming an

287 Galectin modulation of GluK2 kainate receptors was dependent upon complex oligosaccha

288 ts the channel properties of the human GluK2 kainate receptor, we have systematically characterized t

289 fferent fibers express Ca(2+)-permeable AMPA/kainate receptors, we utilized kainate-stimulated uptake

290 and growth cone splitting when NMDA and AMPA/kainate receptors were activated.

291 In contrast, when AMPA/kainate receptors were selectively activated, axon growt

292 ese findings place GluRdelta2 among AMPA and kainate receptors, where the dimer interface is not only

293 Hyperpolarizing bipolar cells express AMPA/kainate receptors, whereas depolarizing bipolar cells (D

294 In contrast, the lesser-studied kainate receptors, which are often present at both pre-

295 promoting the insertion and stabilization of kainate receptors, which may be important for tuning neu

296 on of the CRH system following activation of kainate receptors, which may result in long-term changes

297 also GluK1/GluK5 and GluK2/GluK5 heteromeric kainate receptors with equal potency.

298 Pharmacological blockade of AMPA-kainate receptors with systemic NBQX, or selective AMPA

299 no-terminal domain tetramer in AMPA, but not kainate, receptors with a two-fold to four-fold symmetry

300 channel properties of recombinant and native kainate receptors without affecting trafficking of the r