ライフサイエンスコーパス: PDE6

1 on of cyclic nucleotide phosphodiesterase 6 (PDE6).

2 visual effector enzyme phosphodiesterase-6 (PDE6).

3 s due to defective cGMP phosphodiesterase-6 (PDE6).

4 te may be regulation of phosphodiesterase 6 (PDE6).

5 phototransduction, cGMP phosphodiesterase 6 (PDE6).

6 ily of cyclic nucleotide phosphodiesterases (PDE6).

7 r G-protein effector cGMP phosphodiesterase (PDE6).

8 cones indicating functional substitution of PDE6.

9 a dynamic equilibrium between transducin and PDE6.

10 binding affinity to levels characteristic of PDE6.

11 distinct mechanisms of Pgamma inhibition of PDE6.

12 ion of the distinct isoforms of rod and cone PDE6.

13 5 inhibitors to probe the catalytic sites of PDE6.

14 rim marker peripherin-2 and endogenous frog PDE6.

15 ion between the GAF and catalytic domains in PDE6.

16 the cGMP-bound GAF A domain of chicken cone PDE6.

17 own about direct allosteric communication of PDE6.

18 Gt(alpha)*-GTPgammaS-mediated activation of PDE6.

19 ificity of the interaction between GARP2 and PDE6.

20 ors was determined for purified rod and cone PDE6.

21 evated cGMP levels, but none fully inhibited PDE6.

22 ubunit during the folding and/or assembly of PDE6.

23 ically with the regulatory Pgamma subunit of PDE6.

24 ctively activate cone-specific PDE6 than rod PDE6.

25 assembly of retinal cGMP phosphodiesterase, PDE6.

26 ha)*-GTPgammaS to activate the reconstituted PDE6.

27 tic activity of heterologously expressed rod PDE6.

28 presence of the inhibitory Pgamma-subunit of PDE6.

29 that the multimeric rod phosphodiesterase 6 (PDE6), a prenylated protein and RCE1 substrate, was unab

30 to defects in rod-specific phosphodiesterase PDE6, a tetramer consisting of catalytic (PDE6alpha and

31 class-specific differences between PDE5 and PDE6 account for the biochemical and pharmacological dif

32 sphorylation sites can influence the rate of PDE6 activation and deactivation and raise the possibili

33 of detailed structural information about the PDE6 activation mechanism hampers efforts to develop the

34 ous rod or cone Pgamma variants and analyzed PDE6 activation upon addition of the activated transduci

35 ew insights into the molecular mechanisms of PDE6 activation.

36 ing increases in proportion to the extent of PDE6 activation.

37 providing insight into the regulation of the PDE6 activation/deactivation cycle.

38 te regulatory control of the lifetime of rod PDE6 activation/deactivation during visual signaling, as

39 Although major steps in the PDE6 activation/deactivation pathway have been identifie

40 a)) to PDE6, displacement of Pgamma from the PDE6 active site, and enzyme activation.

41 ic manner, with only one-half of the maximum PDE6 activity efficiently attained during visual excitat

42 TPR domain of AIPL1 also failed to modulate PDE6 activity efficiently.

43 f GARP2 for PDE6 and its ability to regulate PDE6 activity in its dark-adapted state suggest a novel

44 for a nonsense Pde6b(rd1) allele, absence of PDE6 activity is associated with retinal disease similar

45 In the dark, PDE6 activity is suppressed by its inhibitory gamma-subu

46 exhibit a hypomorphic phenotype with partial PDE6 activity that may result in an increased Ca(2+) to

47 Before degeneration, PDE6beta expression and PDE6 activity were reduced.

48 ad to the loss of both HSP90 interaction and PDE6 activity, confirming these variants cause LCA.

49 e dispensable for both HSP90 interaction and PDE6 activity.

50 gulation of photoreceptor phosphodiesterase (PDE6) activity is responsible for the speed, sensitivity

51 To elucidate the structural determinants of PDE6 allosteric regulators, we biochemically characteriz

52 lts show that the PDE6gamma binding sites of PDE6 alpha and beta are accessible to excess (presumably

53 rod PDE6 (alphabeta) and the absence of cone PDE6 (alpha') catalytic subunits.

54 alphabeta), while the catalytic core of cone PDE6 (alpha') is a homodimer.

55 aches, we demonstrated the expression of rod PDE6 (alphabeta) and the absence of cone PDE6 (alpha') c

56 role as a chaperone of phosphodiesterase 6 (PDE6), an effector enzyme of the visual transduction cas

57 lacked interaction with the gamma-subunit of PDE6, an effector protein in phototransduction.

58 Following reconstitution of PDE6 and activated Gt(alpha) with liposomes and identifi

59 rotein-like 1 (AIPL1), and mutations in both PDE6 and AIPL1 can cause a severe form of blindness.

60 Progress in research on PDE6 and AIPL1 has been severely hampered by failure to

61 -binding protein with the prenyl moieties of PDE6 and AIPL1-TPR with the Pgamma subunit during the fo

62 wed a high degree of homology with mammalian PDE6 and equally distant relationships with the rod and

63 a-GDP, the PDE6gamma may dissociate from the PDE6 and exchange with a cytoplasmic pool.

64 Lack of interaction disrupts trafficking of PDE6 and GRK1 to their destination, the photoreceptor ou

65 eracts with the catalytic subunit (alpha) of PDE6 and is needed for the proper assembly of functional

66 The high binding affinity of GARP2 for PDE6 and its ability to regulate PDE6 activity in its da

67 sential for the intracellular trafficking of PDE6 and survival of photoreceptor cells.

68 rated that AIPL1 is an obligate chaperone of PDE6 and that it enables low yield functional folding of

69 ons with the catalytic alphabeta-subunits of PDE6 and the alpha-subunit of transducin (alpha(t)).

70 utations in AIPL1 are thought to destabilize PDE6 and thereby cause Leber congenital amaurosis type 4

71 alpha(t)GTPgammaS co-immunoprecipitated with PDE6 and vice versa in a Pgamma-dependent manner.

72 Therefore, FAT10 may contribute to loss of PDE6 and, as a consequence, degeneration of retinal cell

73 robust decrease in rod phosphodiesterase 6 (PDE6) and G-protein receptor kinase-1 (GRK1) levels.

74 y the opposing actions of phosphodiesterase (PDE6) and retinal guanylyl cyclases (GCs), and mutations

75 f rhodopsin, prenylated phosphodiesterase-6 (PDE6), and intraflagellar transport protein-88 (IFT88).

76 A map revealed previously unseen features of PDE6, and each domain was readily fit with high resoluti

77 Transducin activation of PDE6 appears to require interaction with both the C term

78 he idea that multiple structural elements of PDE6 are highly susceptible to misfolding during heterol

79 Although AIPL1 and PDE6 are known to interact via the FK506-binding protein

80 spontaneously activated and light-activated PDE6 are modulated.

81 s expressed in human retina and identify rod PDE6 as a retina-specific substrate of FAT10 conjugation

82 noncatalytic cGMP to the GAFa domains of rod PDE6, as well as a stable open conformation of Palphabet

83 velop therapeutic interventions for managing PDE6-associated retinal diseases.

84 e show that the catalytic subunit (alpha) of PDE6 associates with AIPL1 in retinal extracts.

85 e demonstrated that GARP2 is a high affinity PDE6-binding protein and that PDE6 co-purifies with GARP

86 ndant in retinal cells, selectively released PDE6 (but not GARP2) from rod outer segment membranes, d

87 no acids decreased the Michaelis constant of PDE6 by 2.5-fold.

88 the differential activation of rod and cone PDE6 by transducin.

89 ivation of the cyclic GMP phosphodiesterase (PDE6) by transducin is the central event of visual signa

90 n (PrBP/delta) indicated the location of the PDE6 C-terminal prenylations.

91 We conclude that either rod or cone PDE6 can effectively couple to the cone phototransductio

92 titutive activation of the phosphodiesterase PDE6 cascade in darkness.

93 Transducin activation of PDE6 catalysis critically depends on the presence of Ile

94 subunit (Pgamma), known to directly inhibit PDE6 catalysis, was increased approximately 2-fold by li

95 sducin relieves this inhibition and enhances PDE6 catalysis.

96 ngaging the PDE6 hetero-tetramer at both the PDE6 catalytic core and the PDEgamma subunits, driving e

97 Rod PDE6 catalytic core is composed of two distinct subunits

98 identical PDE6alpha' subunits form the cone PDE6 catalytic core.

99 integrative structural determination of the PDE6 catalytic dimer (alphabeta), based primarily on che

100 In solution, the PDE6 catalytic dimer (Palphabeta) exhibits a more asymme

101 Next we reconstituted rod PDE6 catalytic dimer (Palphabeta) with various rod or co

102 to bind to either the PDE6 holoenzyme or the PDE6 catalytic dimer reconstituted with Pgamma, consiste

103 ange was detected upon ligand binding to the PDE6 catalytic dimer.

104 PDE6 fail to exceed 50% of the value for the PDE6 catalytic dimer.

105 antly alter catalysis of the fully activated PDE6 catalytic dimer.

106 Here, crystal structures of a chimaeric PDE5/PDE6 catalytic domain (PDE5/6cd) complexed with sildenaf

107 s-of-function mutagenesis of a chimeric PDE5/PDE6 catalytic domain and gain-of-function mutagenesis o

108 The PDE6 catalytic subunit contains a catalytic domain and r

109 It is not known whether this difference in PDE6 catalytic subunit identity contributes to the funct

110 A single PDE6 catalytic subunit transcript was found in the sea l

111 ariations between PDE6 subunits preclude rod PDE6 catalytic subunits from coupling to the cone photot

112 ng implies that the retention of the -AAX in PDE6 catalytic subunits in Rce1(-/-) mice is responsible

113 d rhodopsin kinase (GRK1) and prenylated rod PDE6 catalytic subunits partially mislocalized in Pde6d(

114 Although rod and cone PDE6 catalytic subunits share a similar domain organizat

115 When PDE6 catalytic subunits were reconstituted with portions

116 On the other hand, FAT10 inhibits PDE6 cGMP hydrolyzing activity by noncovalently interact

117 o effect on HSP90 binding, the modulation of PDE6 cGMP levels was impaired.

118 aG38D function, its poor ability to activate PDE6 (cGMP phosphodiesterase) and decreased GTPase activ

119 high affinity PDE6-binding protein and that PDE6 co-purifies with GARP2 during several stages of chr

120 el for the activated state of the transducin-PDE6 complex during visual excitation, enhancing our und

121 ults, we present a model of the larger AIPL1-PDE6 complex.

122 yo-electron microscopy (cryoEM) structure of PDE6 complexed to GTP-bound Galpha(T).

123 c regulators, we biochemically characterized PDE6 complexes in various allosteric states (Palphabeta,

124 domain, cone PDE6 is a homodimer whereas rod PDE6 consists of two homologous catalytic subunits.

125 Holo-PDE6 consists of two similar catalytic subunits (Palphab

126 PDE6 contains two regulatory GAF domains, of which one (

127 light produces a Ca(2+)-mediated decrease in PDE6 decay rate, with the novel feature that both sponta

128 Stop), which allows us to temporally correct PDE6-deficiency.

129 ated transducin alpha-subunit (Gt(alpha)) to PDE6, displacement of Pgamma from the PDE6 active site,

130 a (PDE6 gamma) inhibitory subunit of the rod PDE6 effector enzyme plays a central role in the turning

131 * and activation of the phosphodiesterase 6 (PDE6) effector molecule occurs with less gain.

132 Affected retinas lacked PDE6 enzymatic activity.

133 The rod PDE6 enzyme expressed in cone cells is active and contri

134 cone photoreceptor neurons utilize discrete PDE6 enzymes that are crucial for phototransduction.

135 hibited trypsin-activated lamprey and bovine PDE6 enzymes.

136 In addition, rod PDE6 expressed in cone cells couples to the light signal

137 re compared with rd1/+ rods based on similar PDE6 expression.

138 rafficking of M-cone opsin and restored cone PDE6 expression.

139 hydrolytic activity of transducin-activated PDE6 fail to exceed 50% of the value for the PDE6 cataly

140 To understand the evolution of the PDE6 family, we have examined PDE6 in lamprey, an ancien

141 t AIPL1 stabilizes the FAT10 monomer and the PDE6-FAT10 conjugate.

142 we elucidated the functional consequences of PDE6 FAT10ylation.

143 The binding affinity of PDE6 for pharmacological inhibitors or for the C-termina

144 one hand, we demonstrate that FAT10 targets PDE6 for proteasomal degradation by formation of a coval

145 somal degradation, but whether FAT10 affects PDE6 function or turnover is unknown.

146 e are caused by a loss in phosphodiesterase (PDE6) function.

147 tivity by noncovalently interacting with the PDE6 GAFa and catalytic domains.

148 Several studies have shown that PDE6 gamma can be phosphorylated at two threonines, T22

149 ents suggest that the polycationic domain of PDE6 gamma containing these two phosphorylation sites ca

150 that phosphorylation or dephosphorylation of PDE6 gamma could modify the time course of transduction,

151 hydrolysis of the second messenger cGMP, and PDE6 gamma in association with RGS9-1 and the other GAP

152 isual transduction cascade, since binding of PDE6 gamma to the transducin alpha subunit (T alpha) ini

153 The phosphodiesterase 6 gamma (PDE6 gamma) inhibitory subunit of the rod PDE6 effector

154 C-B inhibition by the cone- and rod-specific PDE6 gamma-subunits (Pgamma) were comparable.

155 ntly inhibited by the cone- and rod-specific PDE6 gamma-subunits.

156 ts point to a high degree of conservation of PDE6 genes during the vertebrate evolution.

157 a) and PDE6 subunits, we determined that the PDE6-Gt(alpha) protein complex consists of two Gt(alpha)

158 compound with high specificity for PDE5 over PDE6, had a similar action.

159 understanding the structure and function of PDE6 has been hindered by lack of an expression system o

160 catalytic cGMP binding to the GAF domains of PDE6 has been localized to amino acids 27-30 of Pgamma.

161 eals two Galpha(T).GTP subunits engaging the PDE6 hetero-tetramer at both the PDE6 catalytic core and

162 esults demonstrate that both subunits of the PDE6 heterodimer are able to bind ligands to the enzyme

163 he alpha- and beta-subunits of the activated PDE6 heterodimer.

164 The functional significance of rod PDE6 heterodimerization and conserved differences betwee

165 edge about the molecular organization of the PDE6 holoenzyme (alphabetagammagamma).

166 The rod PDE6 holoenzyme (Palphabetagamma(2)) is composed of a ca

167 e cGMP-dependent regulation mechanism of the PDE6 holoenzyme and its inhibition through Pgamma bindin

168 activity of the nonactivated, membrane-bound PDE6 holoenzyme at concentrations equivalent to its endo

169 Here, we characterize the PDE6 holoenzyme by integrative structural determination

170 The rod PDE6 holoenzyme consists of two catalytic subunits (Palp

171 [(3)H]vardenafil fails to bind to either the PDE6 holoenzyme or the PDE6 catalytic dimer reconstitute

172 Binding of activated transducin to PDE6 holoenzyme resulted in a concentration-dependent in

173 PrBP/delta bound to the PDE6 holoenzyme with high affinity (K(D) = 6.2 nm) and i

174 transducin activation of membrane-associated PDE6 holoenzyme, [(3)H]vardenafil binding increases in p

175 binds cGMP and regulates the activity of the PDE6 holoenzyme.

176 in quantitatively separating GARP2 from the PDE6 holoenzyme.

177 retinal cyclic GMP (cGMP) phosphodiesterase (PDE6) holoenzyme.

178 re, transducin relieves Pgamma inhibition of PDE6 in a biphasic manner, with only one-half of the max

179 ly hampered by failure to express functional PDE6 in a heterologous expression system.

180 A structure of PDE6 in complex with prenyl-binding protein (PrBP/delta)

181 The structure of holo-PDE6 in complex with the ROS-1 antibody Fab fragment was

182 ith retina-specific Rce1 knock-out mice, rod PDE6 in Icmt-deficient mice trafficked normally to the p

183 olution of the PDE6 family, we have examined PDE6 in lamprey, an ancient vertebrate group.

184 a transgenic mouse model that expresses cone PDE6 in rods and show that the cone PDE6 isoform is part

185 able to reverse the transducin activation of PDE6 (in contrast to a previous study) nor did it signif

186 examined the role of cGMP phosphodiesterase (PDE6) in this difference by expressing cone PDE6 (PDE6C)

187 ow the determinants and the mechanism of the PDE6 inhibition by Pgamma and suggest the conformational

188 bution of the H-loop-M-loop interface to the PDE6 inhibition by the Pgamma C-terminus.

189 th fewer adverse side effects resulting from PDE6 inhibition.

190 How the PDE6 inhibitory gamma-subunit (Pgamma) interacts with th

191 o GAFab induced upon binding of cGMP and the PDE6 inhibitory gamma-subunit (Pgamma).

192 In contrast, two different PDE6 inhibitory Pgamma subunits, a cone-type Pgamma1 and

193 The retinal phosphodiesterase (PDE6) inhibitory gamma-subunit (PDEgamma) plays a centra

194 ion state, the cyclic GMP phosphodiesterase (PDE6) inhibitory gamma-subunit (PDEgamma) stimulates GTP

195 gion of Pgamma is a primary docking site for PDE6-interacting proteins involved in the activation/ina

196 The cGMP phosphodiesterase (PDE6) involved in visual transduction in photoreceptor c

197 (GAFa and GAFb) and a catalytic domain, cone PDE6 is a homodimer whereas rod PDE6 consists of two hom

198 The catalytic core of rod PDE6 is a unique heterodimer of PDE6A and PDE6B catalyti

199 Rod PDE6 is composed of heterodimeric catalytic subunits (al

200 r demonstrate that this rapid degradation of PDE6 is due to the essential role of AIPL1 in the proper

201 PDE6 is membrane associated through isoprenyl membrane a

202 We conclude that allosteric regulation of PDE6 is more complex than for PDE5 and is dependent on i

203 Interestingly, we also found that functional PDE6 is required for trafficking of M-opsin to cone oute

204 icance of cGMP binding to the GAF domains of PDE6 is unknown.

205 Rod cGMP phosphodiesterase 6 (PDE6) is a key enzyme of the phototransduction cascade,

206 Phosphodiesterase-6 (PDE6) is a multisubunit enzyme that plays a key role in

207 gulation of photoreceptor phosphodiesterase (PDE6) is controlled by both allosteric mechanisms and ex

208 Phosphodiesterase-6 (PDE6) is key to both phototransduction and health of rod

209 Photoreceptor phosphodiesterase (PDE6) is the central effector enzyme in the visual excit

210 Photoreceptor phosphodiesterase (PDE6) is the central effector enzyme in visual excitatio

211 Photoreceptor phosphodiesterase 6 (PDE6) is the central effector of the visual excitation p

212 Photoreceptor cGMP phosphodiesterase (PDE6) is the central enzyme in the visual transduction c

213 Phosphodiesterase 6 (PDE6) is the effector enzyme in the phototransduction ca

214 Phosphodiesterase-6 (PDE6) is the key effector enzyme of the phototransductio

215 Phosphodiesterase-6 (PDE6) is the key effector enzyme of the vertebrate photo

216 of rod photoreceptor cGMP phosphodiesterase (PDE6) is the presence of inhibitory subunits (Pgamma), w

217 Retinal photoreceptor phosphodiesterase (PDE6) is unique among the phosphodiesterase enzyme famil

218 ransduction cascade, cGMP phosphodiesterase (PDE6), is regulated by its gamma-subunit (Pgamma), whose

219 hosphodiesterase of rod photoreceptor cells, PDE6, is the key effector enzyme in phototransduction.

220 ses cone PDE6 in rods and show that the cone PDE6 isoform is partially responsible for the difference

221 of cGMP but is not strictly conserved among PDE6 isoforms.

222 immunohistochemistry, and assay for retinal PDE6 levels and enzymatic activity.

223 a robust pharmacokinetic profile without any PDE6 liability.

224 DE6gamma remains attached to the rest of the PDE6 molecule, but after conversion of Talpha-GTP to Tal

225 indicating that some basic regulation of the PDE6 multisubunit enzyme was maintained albeit by a unkn

226 gs rod survival caused by elevated cGMP in a PDE6 mutant mouse model.

227 Previous work using viral gene therapy on PDE6-mutant mouse models demonstrated photoreceptors can

228 ated cGMP and Ca2+, which are induced by the Pde6 mutation.

229 way in both rod and cone photoreceptors, and PDE6 mutations that alter PDE6 structure or regulation c

230 the mechanisms of visual diseases linked to PDE6 mutations.

231 ed a cone-dominated mouse model lacking cone PDE6 (Nrl(-/-) cpfl1).

232 linked to the highly reduced levels of cone PDE6 observed in the hAIPL1 transgenic mice.

233 metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement.

234 defects in photoreceptor phosphodiesterase (PDE6) or regulation of retinal guanylyl cyclase (retGC).

235 from photoreceptors by the guanylate cyclase/PDE6 pair in phototransduction.

236 one PDE6 (PDE6C) in rd1/rd1 rods lacking rod PDE6 (PDE6AB) using transgenic mice.

237 (PDE6) in this difference by expressing cone PDE6 (PDE6C) in rd1/rd1 rods lacking rod PDE6 (PDE6AB) u

238 Identification of the determinants for the PDE6-Pgamma interaction offers insights into the evoluti

239 PDE6 (phosphodiesterase-6) is the effector molecule in t

240 Phosphodiesterase-6 (PDE6) plays a central role in both rod and cone phototra

241 The stoichiometry of PDE6-PrBP/delta binding and the mechanism by which the P

242 delta binding and the mechanism by which the PDE6-PrBP/delta complex assembles have not been fully ch

243 ve developed a rapid purification method for PDE6-PrBP/delta from bovine rod outer segments utilizing

244 PDE6 present in the inner segment of Rce1-deficient phot

245 trate reduced levels of the mutant AIPL1 and PDE6 proteins in patient organoids, corroborating the fi

246 iated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that

247 The photoreceptor phosphodiesterase (PDE6) regulates the intracellular levels of the second m

248 een identified, mechanistic understanding of PDE6 regulation is limited by the lack of knowledge abou

249 Proper folding of PDE6 relies on the chaperone activity of aryl hydrocarbo

250 which AIPL1 and Pgamma are co-expressed with PDE6 represents an effective tool for probing structure-

251 used to quantify [(3)H]vardenafil binding to PDE6 required histone II-AS to stabilize drug binding to

252 t, the half-maximal activation of bovine rod PDE6 required markedly higher concentrations of Galpha(t

253 ) with the corresponding class-specific cone PDE6 residues (P773E, I778V, E780L, F787W, E796V, D803P,

254 Introduction of PDE6 residues into the background of the PDE5 protein se

255 ting vascular smooth muscle contraction) and PDE6 (responsible for regulating visual transduction in

256 his disease, defects in the alpha-subunit of PDE6 result in a progressive loss of photoreceptors and

257 The lamprey PDE6 sequence showed a high degree of homology with mamm

258 Because PDE6 shares structural and pharmacological similarities

259 This analysis revealed the key role of PDE6-specific residues within the catalytic domain M-loo

260 raction with HSP90 and modulate the rod cGMP PDE6 stability and activity.

261 entrifuge, we examined allosteric changes in PDE6 structure and protein-protein interactions with its

262 hotoreceptors, and PDE6 mutations that alter PDE6 structure or regulation can result in several human

263 The catalytic PDE6 subunit was present in the photoreceptors of both t

264 ed as a putative rod cGMP phosphodiesterase (PDE6) subunit in the retina, where it is relatively abun

265 Prenylated PDE6 subunits and G-protein coupled receptor kinase 1 (G

266 arly shows that in the absence of AIPL1, rod PDE6 subunits are rapidly degraded by proteasomes.

267 basis for interpreting how mutations in rod PDE6 subunits can lead to retinal diseases.

268 cial link between AIPL1 and the stability of PDE6 subunits is not known.

269 It is not known if variations between PDE6 subunits preclude rod PDE6 catalytic subunits from

270 r utilizes discrete catalytic and inhibitory PDE6 subunits to fulfill its physiological tasks, i.e. t

271 t the affected retinas also lacked the other PDE6 subunits, suggesting expression of PDE6A is essenti

272 ication of cross-links between Gt(alpha) and PDE6 subunits, we determined that the PDE6-Gt(alpha) pro

273 at AIPL1 is not involved in the synthesis of PDE6 subunits.

274 ed for the proper assembly of functional rod PDE6 subunits.

275 he proper assembly of synthesized individual PDE6 subunits.

276 ion in levels of rod cGMP phosphodiesterase (PDE6) subunits (alpha, beta, and gamma).

277 Furthermore, assembled phosphodiesterase-6 (PDE6) subunits, rod transducin and G-protein receptor ki

278 y to more effectively activate cone-specific PDE6 than rod PDE6.

279 ass-specific differences in PDE5 versus cone PDE6 that contribute to the accelerated catalytic effici

280 s between the two Galpha(T).GTP subunits and PDE6 that supports an alternating-site catalytic mechani

281 tify functional differences between PDE5 and PDE6 that will accelerate efforts to develop the next ge

282 we examined the role of distinct isoforms of PDE6, the effector enzyme in phototransduction, in these

283 rminus of Pgamma occludes the active site of PDE6, thereby preventing hydrolysis of cGMP.

284 a regulator of spontaneous activation of rod PDE6, thereby serving to lower rod photoreceptor "dark n

285 cin can stimulate the hydrolytic activity of PDE6 to its maximum extent.

286 involves the binding of isoprenyl groups on PDE6 to the FKBP domain of AIPL1.

287 is responsible for blocking the movement of PDE6 to the outer segment.

288 with its two targets facilitate the alpha(t).PDE6 "transducisome" formation.

289 ents downstream of the Frizzled-2/G alpha t2/PDE6 triad activated in response to Wnt5a, we observed a

290 were eliminated when the beta-subunit of rod PDE6 was removed (Nrl(-/-) cpfl1 rd).

291 of G-protein with Rh* and the activation of PDE6, we investigated the mechanism of the amplification

292 pus laevis is a unique expression system for PDE6 well suited for analysis of the mechanisms of visua

293 e to the accelerated catalytic efficiency of PDE6 were identified but required heterologous expressio

294 the correct assembly of phosphodiesterase 6 (PDE6), which is a pivotal effector enzyme for phototrans

295 d the cyclic GMP (cGMP) phosphodiesterase 6 (PDE6), which stimulates cGMP hydrolysis, leading to hype

296 e conformational changes and interactions of PDE6 with known interacting proteins are poorly understo

297 asis for developing allosteric activators of PDE6 with therapeutic implications for halting the progr

298 In addition, prolonged incubation of PDE6 with vardenafil or sildenafil (but not 3-isobutyl-1

299 hibitory interaction of phosphodiesterase-6 (PDE6) with its gamma-subunit (Pgamma) is pivotal in vert

300 The interaction of phosphodiesterase 6 (PDE6) with its inhibitory Pgamma-subunits (Pgamma) is un