ABCMdb

ABCC8 p.Glu128Trp

None has been submitted yet.

Publications

PMID: 21321069 [PubMed] Pratt EB et al: "N-terminal transmembrane domain of SUR1 controls gating of Kir6.2 by modulating channel sensitivity to PIP2."

No. Sentence Comment

23 Further supporting this notion, the E128W mutation in full-length channels resulted in channel inactivation that was prevented or reversed by exogenous PIP2. Login to comment
37 In contrast, E128K disrupts functional coupling between TMD0 and Kir6.2 by abrogating the effects of SUR1 on channel response to PIP2. Moreover, the mutation E128W leads to spontaneous current inactivation that can be prevented or reversed by PIP2. Login to comment
215 Inactivation of E128W channels could be recovered by exposure to high concentrations of ATP (1, 3, or 5 mM) in a time-dependent manner, such that lengthening the time of ATP ex-posure resulted in more current when the patch was reexposed to nucleotide-free solution (Fig. 8, A and B). Login to comment
216 Further, exposure of the E128W patches to PIP2 slowed or reversed the inactivation as well as potentiated the ATP-induced "resetting" of channel activity (Fig. 8 C). Login to comment
217 These results indicate that E128W causes KATP channel inactivation by destabilizing PIP2-KATP channel interactions, and that ATP exposure re- est-ablishes the interactions as seen in the transient channel activity when the inhibitory effect of ATP is removed. Login to comment
225 The E128W mutation in SUR1 causes inactivation in full-length channels that can be recovered by PIP2 and by exposure and subsequent removal of ATP Additional evidence supporting the involvement of E128 in mediating channel response to PIP2 came from the intriguing phenotype observed with the E128W mutation. Login to comment
243 Although the exact location of R74 with respect to the membrane has not Figure 8. E128W causes KATP channel inactivation that can be recovered by ATP exposure and subsequent removal of ATP and can be reversed by PIP2. Login to comment
249 (B) The ability of high concentrations (1-5 mM) of ATP to reset the E128W KATP channel is illustrated by this scatter plot. Login to comment
254 (C) Representative trace showing that exposure of the E128W KATP channels to 5 µM PIP2 (striped bars) decreased and reversed inactivation as well as increased the efficacy of ATP (black lines, 5 mM) to reset the channel. Login to comment
270 (B) The E128W mutation destabilizes the channel in the SUR1-Kir6.2-coupled, PIP2-bound open state, leading to channel inactivation. Login to comment
280 A novel KATP channel inactivation mechanism revealed by the E128W mutation and structural implications The importance of E128 in the structural and functional integrity of KATP channels is further accentuated by the inactivation phenotype of the E128W mutant. Login to comment
282 First, current inactivation induced by E128W is distinct from rundown. Login to comment
283 Second, inactivation caused by E128W is prevented or reversed by PIP2. Login to comment
287 That inactivation induced by E128W is overcome by PIP2 lends strong support to our proposal that E128 plays a critical role in the stabilization of Kir6.2-PIP2 interactions by SUR1. Login to comment
288 In addition, the ATP-dependent recovery from inactivation in the E128W mutant suggests that conformational changes in Kir6.2 tertiary structure of R74K TMD0 and its ability to assemble with Kir6.2 to form channels may be contingent upon the SUR1 structures downstream of TMD0. Login to comment
310 Finally, our discovery of the E128W inactivation mutation provides novel insight into the structural relationship between channel subunits as a function of ATP and PIP2. Login to comment
347 The similar gating properties seen in E128W and Kir6.2 inactivation mutations predicted to alter inter-Kir6.2 subunit interfaces imply that these mutations disrupt normal channel gating via a converging mechanism that is sensitive to both PIP2 and ATP. Login to comment
352 The finding is especially provocative when considered in the context of the SUR1-Kir6.2 KATP channel complex because it opens up the possibility that SUR1 can modulate Kir6.2 conduction primarily through cytoplasmic domain interfaces, such as that mediated by E128. We propose that in KATP channels, SUR1 stabilizes a Kir6.2 structure in the PIP2-bound open state via cytoplasmic interactions, and that the inactivation phenotype of E128W represents transition from a SUR1-coupled conformation to Kir6.2 structures lacking the stabilizing effect of SUR1, as seen in Kir6.2C36. Login to comment
353 ATP binding is envisioned to cause a conformational switch in Kir6.2, such that channels can enter a PIP2-bound open state once ATP is removed.Thus,inthecaseofKir6.2inactivationmutations, ATP reactivates the channel by reestablishing Kir6.2 subunit interface (Lin et al., 2003), and in the case of E128W, by reestablishing SUR1-Kir6.2 interactions necessary for stabilizing channel opening, albeit only briefly (see Fig. 9 B). Login to comment
354 Increasing the concentration of PIP2 in the membrane is expected to shift the equilibrium toward the PIP2-bound open state by mass action, thereby slowing and reversing inactivation as well as boosting the ATP-induced resetting of the channel in both Kir6.2 and E128W-SUR1 inactivation mutants (Figs. Login to comment

PMID: 21654216 [PubMed] Pratt EB et al: "ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 and Kir6.2 with diminished PIP2 sensitivity."

No. Sentence Comment

40 Moreover, another mutation at the same site, E128W, causes rapid destabilization of channel activity that is reversed by PIP2 . Login to comment
86 The ATP-induced conformational change referred to here is analogous to the previously reported effect of ATP on several mutations that cause spontaneous channel inactivation, including E128W in SUR1 and R192E, R301E and R314E in Kir6.2.14,23 In the inactivation mutants, exposure to high concentrations of ATP followed by subsequent washout to remove the inhibitory effect of ATP recovers channels from inactivation and allows channels to open briefly before they inactivate again (this inactivation phenomenon can be seen in the R192E// E128K mutant following removal of ATP, Fig. 2A, middle). Login to comment