KChannelDB: Extraction of mutation data from the literature

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This data was extracted from Medline abstracts and full texts (when available) in an automated manner.

The table below describes different point mutations at a given position and provides links to other documents. The sentence(s) where the point mutations in KCNH2_HUMAN at position 752 were found are listed after the table.

Point mutations at position R752 in KCNH2_HUMAN

ProteinKCNH2_HUMAN (Q12809)    Gene: KCNH2,ERG, ERG1, HERG, HERG    (other point mutations)Swiss-Prot
Cross-reference table
Family page
Protein isoforms4
PositionR752
General numbering (KChannelDB) -
DomainC-term
Family alignments eag related KCNH (Kv10-12)
K+ voltage-gated channels (Kv1-12,Kca2-5)
Potassium channels 6 TMs
Other point mutations at the same position Position 752 in eag related KCNH (Kv10-12) family
Position 740 in K+ voltage-gated channels (Kv1-12,Kca2-5) family
Reference #1Ficker E, Thomas D, Viswanathan PC, Dennis AT, Priori SG, Napolitano C, Memmi M, Wible BA, Kaufman ES, Iyengar S, Schwartz PJ, Rudy Y, Brown AM
Am J Physiol Heart Circ Physiol 2000 Oct;279(4):H1748-56.		Medline
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Point mutationR752W (Not yet checked)
Reference #2Ficker E, Dennis AT, Obejero-Paz CA, Castaldo P, Taglialatela M, Brown AM
J Mol Cell Cardiol 2000 Dec;32(12):2327-37.		Medline
Text sourcePDF full text
Point mutationR752W (Not yet checked)
Reference #3Ficker E, Obejero-Paz CA, Zhao S, Brown AM
J Biol Chem 2002 Feb 15;277(7):4989-98.		Medline
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Point mutationR752W (Not yet checked)
Reference #4Paulussen A, Raes A, Matthijs G, Snyders DJ, Cohen N, Aerssens J
J Biol Chem 2002 Dec 13;277(50):48610-6.		Medline
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Point mutationR752W (Not yet checked)
Reference #5Johnson WH Jr, Yang P, Yang T, Lau YR, Mostella BA, Wolff DJ, Roden DM, Benson DW
Pediatr Res 2003 May;53(5):744-8. Epub 2003 Mar 5.		Medline
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Point mutationR752Q (Not yet checked)
Point mutationR752W (Not yet checked)
Reference #6Ficker E, Dennis AT, Wang L, Brown AM
Circ Res 2003 Jun 27;92(12):e87-100. Epub 2003 May 29.		Medline
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Point mutationR752W (Not yet checked)
Reference #7Anson BD, Ackerman MJ, Tester DJ, Will ML, Delisle BP, Anderson CL, January CT
Am J Physiol Heart Circ Physiol 2004 Jun;286(6):H2434-41. Epub 2004 Feb 19.		Medline
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Point mutationR752W (Not yet checked)

Relevant sentences

Reference #5 (Johnson WH Jr et al.): R752Q
  • Direct bidirectional sequencing of long QT syndrome genes identified a previously unreported HERG missense mutation (R752Q)

  • Three asymptomatic family members were heterozygous for R752Q , and the proband , who manifested ventricular tachycardia in utero , was homozygous

  • R752Q was not found in 100 normal unrelated chromosomes

  • The HERG mutant , R752Q , is associated with a mild phenotype , inas much as family members with a heterozygous mutation appear unaffected

  • Chinese hamster ovary (CHO) cells were transiently transfected with wild-type HERG or HERG mutant (R752Q) cDNA

  • A G to A transition (G2255A) that changed the coding sense from arginine to glutamine (R752Q) was identified in HERG

  • Three asymptomatic family members (I-1 , II-1 , and II-4) were heterozygous for R752Q and the proband (III-1) was homozygous (Fig. 2 )

  • Allele-specific oligonucleotide hybridization (ASO) was used to confirm R752Q and exclude its presence in 100 normal unrelated chromosomes (7)

  • Biophysical characterization of HERG (R752Q)

  • Wild-type HERG generated robust I Kr , but no current was observed with the mutant HERG (R752Q ; two independent clones) (Fig. 3 )

  • Biophysical characteristics of HERG R752Q

  • (B) HERG-R752Q current

  • (C) Current-voltage relationship for wild-type and R752Q tail currents

  • DISCUSSION (image)TOP (image)ABSTRACT (image)INTRODUCTION (image)METHODS (image)RESULTS (image)DISCUSSION (image)NOTES (image)REFERENCES A HERG missense mutation , R752Q , results in absence of I Kr

  • R752Q may result in loss of HERG channel function because of a similar mechanism , or to abnormal gating

  • In either case , as shown in the present report , homozygosity of R752Q results in near-total loss of channel function , i.e. absence of I Kr

Reference #1 (Ficker E et al.): R752W
  • We studied a novel COOH-terminal missense mutation , HERG R752W , which segregated with the disease in a family of 101 genotyped individuals

  • Therefore , HERG R752W represents a new class of trafficking mutants in hLQTS

  • In a large LQT2 family we found a novel COOH-terminal missense mutation , HERG R752W , which was retained in the ER

  • When trafficking was corrected , HERG R752W channels conducted enhanced currents that slightly shortened the cardiac action potential simulated by the Luo-Rudy model of a mammalian ventricular myocyte

  • HERG R752W was prepared by overlap extension PCR , verified by sequencing , and subcloned as a Xho I-BamH I fragment into either full-length HERG-pSP64 or HERG-pCDNA3

  • For the purpose of this study , the formulation of the fast delayed rectifier potassium current , I Kr , was modified to fit our experimental voltage clamp data obtained from HERG-WT and HERG-R752W channels

  • RESULTS (image)TOP (image)ABSTRACT (image)INTRODUCTION (image)MATERIALS AND METHODS (image)RESULTS (image)DISCUSSION (image)REFERENCES HERG R752W was identified in a 31-yr-old woman with a history of syncope who died suddenly

  • Characterization of HERG R752W currents in Xenopus oocytes

  • After injection of equivalent amounts of cRNA , we were surprised to find that mutant HERG R752W channels produced larger outward currents than WT channels (Fig. 1 , A and B)

  • Both WT and R752W produced typical bell-shaped isochronal current-voltage (I-V) relationships (Fig. 1 C)

  • For R752W , the amplitudes were larger and the I-V curve was shifted to more hyperpolarized potentials

  • Compared with the corrected WT , I-V curve threshold and peak for R752W remained shifted (Fig. 1 C) , suggesting that altered gating properties contributed importantly to the larger currents of R752W

  • Coinjection of equal amounts of WT and R752W cRNA produced a summation of current amplitudes at potentials more positive than -20 mV

  • At more hyperpolarized potentials , current amplitudes from the combined injection were not significantly changed from R752W alone despite the increased amount of cRNA injected

  • One explanation might be that below -20 mV , activation rates for R752W / WT heteromultimers are very different from homomultimeric channels (see Fig. 2 C) , thereby producing a complex interaction with current amplitudes as measured in Fig. 1 C

  • HERG R752W is located in the COOH-terminal linker between transmembrane domain S6 and the cyclic-nucleotide binding fold common to all members of the ether-a-go-go gene family with the arginine at this position being highly conserved

  • Macroscopic current recordings from Xenopus oocytes injected with 0.5 ng each of HERG wild-type (WT ; A) or HERG R752W cRNA (B ; RW)

  • D: maximal tail current amplitudes elicited on return to -90 mV after a test pulse to 60 mV were back-extrapolated and used to assess the average number of functional channels expressed in oocytes injected with WT or R752W cRNA

  • Half-maximal inactivation V k was -63.3 ± 1.1 mV for WT and -55.5 ± 1.6 mV for HERG R752W (n = 4)

  • HERG R752W accelerates current activation (A)

  • HERG R752W speeds channel deactivation (D)

  • triangle , Time constants measured on coinjection of equal amounts of WT and R752W cRNA

  • To analyze the gating changes introduced by R752W , we studied steady-state activation and inactivation (Fig. 1 , E and F)

  • Compared with WT , the activation and inactivation curves of R752W were shifted by +11.9 and +7.8 mV , respectively (Fig. 1 F)

  • R752W channels activated much faster than WT channels , and this acceleration contributed to increased outward currents with shorter depolarizations

  • Activation time constants were intermediate between WT and R752W at -20 and 0 mV but approximated values measured for R752W alone at +20 and +40 mV (Fig. 2 C)

  • Coinjections of equal amounts of WT and R752W produced intermediate values for slow time constants

  • For the faster process , coinjections approached values measured for R752W alone at potentials between -90 and -120 mV

  • On the other hand , the faster activation rates of R752W predicted more current during the plateau and a tendency to shorten the cardiac action potential

  • Simulations of the effects of WT HERG R752W current on the cardiac action potential

  • Therefore , we expressed HERG R752W in mammalian HEK293 cells at a physiological temperature of 37°C and used whole cell patch clamp recordings to characterize mutant currents

  • We were not able to detect any HERG-like outward current in HEK293 cells transfected with R752W , although WT current was obtained routinely under identical experimental conditions (Fig. 4 , A and B)

  • Because mutant currents were elicited in Xenopus oocytes and because oocytes are maintained at lower temperatures than mammalian cells , we tested the effect of reduced incubation temperature on expression of R752W

  • After incubation for 2 days at 26°C , large whole cell HERG currents were recorded in cells transfected with R752W cDNA and had an electrophysiological profile similar to that described in Xenopus oocytes (Fig. 4 , C and D)

  • 3.8 mV for HERG WT) reflects faster current activation of HERG R752W

  • To evaluate effects of incubation temperature on current expression , HEK293 cells were transfected with either 2 µg HERG WT or 2 µg HERG R752W cDNA and incubated for 2 days at 26 or 37°C as indicated

  • In coexpression experiments , HEK cells were transfected with either 1 µg HERG WT + 1 µg vector cDNA (coWT37) or 1 µg HERG WT + 1 µg HERG R752W (WT / RW37) cDNA and incubated for 2 days at 37°C

  • These results suggested that R752W was not processed correctly at 37°C and processing resumed when the incubation temperature of mammalian cells was lowered to 26°C

  • In contrast , HERG R752W channel protein synthesized at 37°C was present only in the core-glycosylated 135-kDa form and a somewhat smaller form representing either an unglycosylated form (18 ) or more likely a degradation product (Fig. 5 C)

  • Accordingly , immunostaining of R752W-transfected cells with anti-HERG antibodies produced strong perinuclear staining consistent with the accumulation of protein in the ER

  • When cells transfected with R752W were incubated at 26°C , we detected the 160-kDa band corresponding to the fully mature protein as well as the immature bands

  • The same bands were observed in Western blots of crude membrane fractions from Xenopus oocytes injected with either WT or R752W cRNA

  • Because defects in processing of the temperature-sensitive Delta F508 CFTR protein were partially corrected by chemical chaperones such as glycerol (4 , 24 ) or transcriptional regulators such as 4-phenylbutyrate (4-PB) (20 ) , we tested whether these agents might correct the malfunction of R752W processing

  • In none of these experiments did we observe any change in the glycosylation pattern of R752W incubated at 37°C , whereas protein synthesis was progressively decreased with higher glycerol concentrations (Fig. 5 C)

  • Patch clamp recordings also failed to detect R752W currents in cells incubated for 2 days at 37°C at the different glycerol concentrations

  • Furthermore , treatment of R752W transfected cells with 2.5 mM 4-PBA at 37°C had no effect on processing and no currents were detectable although protein synthesis was substantially increased (Fig. 5 C)

  • In contrast , HERG R752W channel protein synthesized at 37°C was present only in the core-glycosylated form when transfected cells were treated for 24 h in the presence of 5 µM E-4031 (Fig. 5 C)

  • DISCUSSION (image)TOP (image)ABSTRACT (image)INTRODUCTION (image)MATERIALS AND METHODS (image)RESULTS (image)DISCUSSION (image)REFERENCES The electrophysiological phenotype of the processed R752W mutant is characterized by mild changes in gating properties that do not translate into prolongation of the cardiac action potential and hence the QT interval as judged by our simulations

  • The accelerated activation and deactivation kinetics of R752W resembles mutations described previously in the NH2-terminal PAS (Per , Arnt , and Sim) domain of the channel protein , especially HERG R56Q (5 )

  • At reduced temperatures where protein folding might be altered , HERG R752W attained a conformation that ultimately permitted exit from the ER

  • We explored whether chemical chaperones known to stabilize temperature-sensitive mutants were effective in correcting the trafficking defect associated with HERG R752W

  • In CFTR it was shown that glycerol promoted the maturation of mutants K464R and K464A but not of K464W , a mutation with an amino acid substitution similar to the one analyzed in HERG R752W

  • The failure of glycerol treatment to facilitate trafficking of HERG R752W was surprising because trafficking of HERG N470D , a hypomorphic mutation in the transmembrane domain of HERG , was improved by incubation in 10% glycerol (31 )

  • Similarly , the antiarrhythmic drug E-4031 facilitated trafficking of HERG N470D , but was ineffective on the R752W mutant

  • These differences suggest that HERG R752W represents a new and different class of misprocessed mutants with distinct mechanisms responsible for retention of mutations localized to different functional domains of the HERG channel protein

  • Because chemical chaperones were not effective in HERG R752W , we complemented our experiments by treating HEK cells expressing HERG R752W with 4-PB , an analog of the transcriptional regulator butyrate

  • In analogy to experiments in CFTR , we tried to boost expression of HERG R752W to force the mutant by mass action past the ER to the plasma membrane (20 )

  • Although synthesis of HERG R752W was substantially enhanced , we were not able to detect fully glycosylated mature protein

  • In summary , HERG R752W is the first member of a novel class of temperature-sensitive trafficking mutants that do not express any current at 37°C and are resistant to rescue by osmolytes or specific channel ligands

  • Thus , although HERG R752W behaves as a loss-of-function mutation , there is one major difference from hLQT mutations reported heretofore: HERG R752W encodes a fully functional channel protein if it can be made to reach the plasma membrane

Reference #2 (Ficker E et al.): R752W
  • The wild-type glycosylation pattern could not be restored by lowering the incubation temperature to Immunostaining 26 °C or by exposing A561V cells to the specific channel blocker E4031 , as described for trafficking For immunostaining , COS-7 cells were grown on poly-lysine coated coverslips and transfected with deficient mutations such as HERG N470D (rescued by temperature and E4031)12 or HERG R752W Fugene according to manufacturers instructions (Roche Biochemicals)

  • The dashed line represents a model where in mislocalized LQT2 mutants such as HERG N470D addition channel tetramers consisting of 2 wild-type and or R752W were functional after trafficking and 2 mutant subunits (2WT / 2MUT) would be able to reach the plasma membrane

Reference #3 (Ficker E et al.): R752W
  • In LQT2 , expression of two trafficking-deficient mutations , HERG N470D and HERG R752W , at low temperature resulted in incorporation of functional channels in the plasma membrane (6 , 17 )

  • Incubation with chemical chaperones restored trafficking and rescued functional channels for HERG N470D , a mutation in the transmembrane domain , but was completely ineffective for HERG R752W , a mutation in the cyclic nucleotide binding domain

  • Similarly , pharmacological rescue of functional channel protein has been reported for HERG N470D when synthesized in the presence of the methanesulfonanilide E4031 , the antihistamine astemizole , or the prokinetic drug cisapride , whereas E4031 was completely ineffective when incubated with HERG R752W (6 , 17 )

  • Recently , we demonstrated that a temperature-sensitive trafficking mutation located in the cyclic nucleotide domain , HERG R752W , was not rescued by incubation with E4031 at 37 °C (6 )

  • Impaired assembly might explain best why temperature-sensitive HERG proteins such as HERG R752W , F805C , or R823W with mutations in the cyclic nucleotide binding domain cannot be rescued using channel blockers

  • Indeed two of these mutations , HERG R752W and R823W do not exert dominant-negative effects when coexpressed with WT channels , suggesting improper assembly (6 , 41 )

Reference #4 (Paulussen A et al.): R752W
  • For example , trafficking of mutant channels G601S , N470D , and R752W (19-21 ) was restored by lower incubation temperatures , but only G601S and N470D channels were restored by chemical chaperones

  • This hypothesis is supported by the results of Ficker et al. (21 ) , who showed large currents for a trafficking-deficient HERG protein (R752W) in the oocyte expression system as compared with the lack of current in the mammalian expression system

Reference #5 (Johnson WH Jr et al.): R752W
  • Another HERG mutation in codon 752 , R752W , has been reported to abrogate I Kr because the channels do not reach the cell surface (15)

Reference #6 (Ficker E et al.): R752W
  • For the trafficking-deficient LQT2 mutants , hERG R752W and hERG G601S , interactions with Hsp90 and Hsp70 are increased as both mutants remained tightly associated with Hsp90 and Hsp70 in the endoplasmic reticulum

  • Incubation at lower temperature for R752W or with the hERG blocker astemizole for G601S dissociates channel-chaperone complexes and restores trafficking

  • Cell Lines Human embryonic kidney (HEK) 293 cells stably transfected with hERG WT (HEK / hERG WT) , hERG R752W HAex , hERG G601S , and hERG G628S were maintained in DMEM , and 10% fetal bovine serum (FBS) plus penicillin / streptomycin / geneticin at 37°C , 5%CO2

  • Molecular Biology hERG mutations were generated by overlap extension PCR , verified by sequencing , and subcloned into full-length hERG-pcDNA3.6 An HA-epitope tag of the sequence 436TEEGPPATNSEHYPYDVPDYAVTFEECGY (insertion shown in bold , HA epitope underlined) was inserted in the extracellular S1-S2 loop to generate hERG WT HAex and hERG R752W HAex

  • Metabolic Labeling and Im munoprecipitation One to 2 days after plating of stable cell lines (HEK hERG WT , hERG R752W HAex , hERG G601S , and hERG G628S: cell lines were selected for comparable expression levels of hERG protein using Western blotting) , cells were starved in methionine / cysteine-free medium for 30 minutes and then pulse-labeled for 30 or 60 minutes in 100 to 150 µCi / mL [35S]-methionine / cysteine (EXPRESS [35S] Protein Labeling Mix , Dupont NEN) containing medium

  • Interactions Between Chaperones and LQT2 Mutant hERG Channels Are Altered To determine whether Hsp / c70 and Hsp90 bind to WT channels and LQT2 mutant channels differentially , we analyzed the interaction of three different LQT2 mutations , hERG R752W , 6 hERG G601S , 33 , 34 and hERG G628S , 3 , 4 with these chaperones

  • First , we examined the temperature-sensitive , trafficking-deficient LQT2 mutation hERG R752W (Figure 8 A)

  • hERG R752W is in the cytoplasmic , C-terminal cNBD domain of the channel protein

  • At physiological temperature (37°C) , hERG R752W is retained in the ER and no mature , fully glycosylated protein is generated in pulse-chase experiments (Figures 8A and 9 (image) A)

  • When im munoprecipitations with anti-Hsp / c70 or Hsp90 antisera were performed immediately after radiolabeling (t = 0 hour) , core-glycosylated R752W mutant protein could be isolated together with either Hsp90 or Hsp / c70

  • Conversely , in im munoprecipitations with anti-hERG antibody , we were able to detect complexes formed by core-glycosylated R752W protein with both Hsp90 and Hsp / c70 as major constituents together with several smaller not yet identified protein bands (Figure 8 A)

  • In these experiments , we found that HERG R752W formed complexes with both Hsp90 and Hsp / c70 during the entire chase period analyzed (Figure 8 A)

  • To determine the abundance of channel-chaperone complexes and time-dependent changes in their composition more precisely , we first quantified the amount of hERG R752W protein that could be im munoprecipitated with either Hsp / c70 or Hsp90 antibody using a PhosphorImager

  • This normalization procedure was necessary because hERG R752W protein decayed along a complex time course with a half-life of about 6 hours during pulse-chase experiments (Figure 9 A)

  • When compared with newly synthesized WT channels (at t = 0 hour) , hERG R752W-Hsp90 complexes were about 2.6-fold more abundant , reflecting most likely discrete intermediates of the folding pathway and subtle folding defects of the mutant

  • Moreover , chaperone association remained constant over time for R752W , whereas both Hsp90 and Hsp / c70 interacted only with newly synthesized hERG WT protein (t = 0 hour) but not with mature fully glycosylated WT channels (t = 6 hours ; Figure 9 B)

  • Chaperone interactions similar to the one described for hERG R752W analyzed at 37°C were also detected for the LQT2 mutant hERG A561V , which is strictly retained in the ER and rapidly degraded in the proteasome (see online Figure S2).5 , 7 View larger version (41K): [in this window] [in a new window]   Figure 8

  • Analysis of chaperone complexes formed with the trafficking-deficient LQT2 mutant hERG R752W

  • A , Im munoprecipitation of hERG R752W protein with anti-hERG , anti-Hsp90 , and anti Hsp / c70 antibodies

  • At all time points analyzed , hERG R752W was present in its core-glycosylated (cg) form only

  • B , Chaperone complexes formed with hERG R752W protein after synthesis and chase at a lower incubation temperature of 26°C

  • At 26°C , a fraction of radiolabeled hERG R752W was slowly converted to the fully glycosylated (fg) mature form of the channel protein (IP hERG ; time points at 16 and 24 hours)

  • Quantitative analysis of hERG WT and hERG R752W processing

  • A , Pulse-chase analysis of hERG R752W processing at 37°C

  • hERG R752W protein was isolated by im munoprecipitation either immediately after radiolabeling or at the end of the different chase periods indicated (see Figure 8 A)

  • Image densities of the core-glycosylated 135-kDa form representing hERG R752W at 37°C were determined using a Phosphor-Imager and normalized

  • B , Time-dependent changes in chaperone association determined for hERG WT and hERG R752W

  • For hERG R752W , the stability of hERG channel / chaperone complexes was prolonged as indicated by time-independent association quotients

  • C , Pulse-chase analysis of hERG WT and hERG R752W at 26°C

  • Note that at 26°C , a small fraction of hERG R752W was converted into the fully glycosylated 155-kDa protein form (see Figure 8 B)

  • At 26°C , chaperone association was reduced with time for both hERG WT and hERG R752W

  • Given the differences in chaperone association observed between trafficking-competent WT channels and trafficking-deficient R752W channels at 37°C , we asked how restoration of trafficking in R752W by incubation at low temperature (26°C) affected the formation and stability of R752W channel-chaperone complexes

  • At 26°C , generation of fully glycosylated hERG protein was not only slowed down for R752W but also for hERG WT channels

  • Fully glycosylated hERG R752W protein was generated with the same kinetics as WT protein in pulse-chase experiments performed at 26°C (Figure 9 C)

  • However , we noted a major difference in the stability of core-glycosylated hERG WT and R752W protein forms

  • Although the amount of core-glycosylated WT protein was stable for about 10 hours after synthesis , hERG R752W was being degraded immediately after labeling

  • The fast degradation of core-glycosylated hERG R752W might help to explain why little R752W channel protein was ultimately converted into the fully glycosylated cell surface form at 26°C (Figure 9 C)

  • Given the small amount of fully glycosylated R752W protein generated and the large pool of core-glycosylated ER-resident R752W protein left even after chase periods of 30 hours , it is not surprising that im munoprecipitations with anti-Hsp / c70 and anti-Hsp90 isolated channel-chaperone complexes in the entire time period analyzed (0 , 16 , and 24 hours ; Figure 8 B)

  • However , when the abundance of R752W chaperone complexes formed at 26°C was quantified over time , we found that association of R752W with Hsp / c70 was reduced in parallel with the generation of fully glycosylated R752W protein by about 1.6-fold (from 0.9 to 0.58) , and with Hsp90 by about 1.4-fold (from 0.5 to 0.35 ; Figure 9 D)

  • At the same time , R752W-Hsp90 complexes were 1.6-fold more abundant at low incubation temperature than corresponding WT complexes (Figure 9 D)

  • Thus , temperature-dependent induction of channel folding and trafficking in R752W was accompanied by a time-dependent reduction in chaperone association , which is , however , less pronounced than the changes observed for WT channels at 26°C

  • These quantitative differences may result mainly from the small amount of fully glycosylated R752W protein ultimately generated at 26°C and indicate that the majority of R752W protein remained in misfolded , trafficking-deficient conformations even at 26°C

  • Because the trafficking defect of hERG R752W was corrected by low incubation temperature only for a small channel population , we decided to analyze a second LQT2 retention mutant , hERG G601S

  • It is interesting to point out that the degree of chaperone association was lower for hERG G601S (association coefficients between 0.1 and 0.4) than for R752W (between 0.5 and 1.1) at 37°C

  • Our failure to detect similar differences for Hsp90 was surprising given our results with hERG R752W

  • Our experiments with hERG R752W and hERG G601S demonstrated that both of these trafficking-deficient LQT2 mutants remained associated with cytosolic Hsp / c70 and Hsp90 chaperones while in the ER

  • For two different LQT2 mutations , hERG R752W and hERG G601S , we demonstrated prolonged association with Hsp90 and Hsp / c70 in the ER

  • In rescue experiments with hERG R752W and G601S , we showed that initiation of productive folding by lowering the incubation temperature or by incubation with pharmacological chaperones led ultimately to the dissociation of channel-chaperone complexes , followed by successful channel export to the cell surface

Reference #7 (Anson BD et al.): R752W
  • Three of these , R752W , S818L , and V822M , have been functionally characterized and shown to be trafficking defective (6 , 16 , 32 )

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F.Horn (kchanneldbcmbi.ru.nl), 17-Aug-2005