ABCMdb

ABCC8 p.Glu1506Gly

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Publications

PMID: 21617188 [PubMed] Mannikko R et al: "Mutations of the same conserved glutamate residue in NBD2 of the sulfonylurea receptor 1 subunit of the KATP channel can result in either hyperinsulinism or neonatal diabetes."

No. Sentence Comment

0 Mutations of the Same Conserved Glutamate Residue in NBD2 of the Sulfonylurea Receptor 1 Subunit of the KATP Channel Can Result in Either Hyperinsulinism or Neonatal Diabetes Roope Männikkö,1 Sarah E. Flanagan,2 Xiuli Sim,1 David Segal,3 Khalid Hussain,4 Sian Ellard,2 Andrew T. Hattersley,2 and Frances M. Ashcroft1 OBJECTIVE-Two novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of the ATP-sensitive K+ channel (KATP channel) sulfonylurea receptor 1 (SUR1) subunit were detected heterozygously in patients with neonatal diabetes. Login to comment
50 Furthermore, the mutation of E1506 to lysine (E1506K) results in reduced channel activation by MgADP and is associated with hyperinsulinism (26,27). Login to comment
51 This article reports our investigation of how the mutation of E1506 to aspartate (E1506D) or glycine (E1506G) results in the opposite clinical condition of neonatal diabetes. Login to comment
96 A small but significant increase in resting current was observed for both homomeric Kir6.2/SUR1-E1506D (homE1506D) and Kir6.2/SUR1-E1506G (homE1506G) channels (Fig. 1). Login to comment
111 This suggests that the neonatal diabetes mutations have little (E1506D) or no (E1506G) effect on expression levels of the KATP channel in the heterozygous state. Login to comment
136 B: Kir6.2/SUR1-E1506D (n = 11), IC50 = 20.1, h = 1.05. Login to comment
137 C: Kir6.2/SUR1-E1506G (n = 10), IC50 = 18.8, h = 0.93. Login to comment
139 E: Kir6.2/SUR1-E1506D (n = 7), IC50 = 8.2, h = 1.00. Login to comment
140 F: Kir6.2/SUR1-E1506G (n = 7), IC50 = 6.9, h = 0.86. Login to comment
179 No increase in current was observed for the Kir6.2-G334D/SUR1-E1506D (G334D/E1506D) or Kir6.2-G334D/SUR1-E1506G (G334D/ E1506G) channels; in contrast, the Kir6.2-G334D/SUR1-E1506K (G334D/E1506K) currents increased 1.5-fold on excision. Login to comment
180 This suggests that the G334D/E1506 and G334D/ E1506K channels were partially blocked under resting conditions in the oocyte, whereas the G334D/E1506D and G334D/E1506G channels were fully open. Login to comment
181 Larger amplitudes were found for the G334D/E1506 (8.5 6 1.9 nA, n = 16) and G334D/E1506K (14 6 1.9 nA, n = 9) currents than for the G334D/E1506D (1.0 6 0.2 nA, n = 11) or G334D/ E1506G (0.8 6 0.2 nA, n = 13) currents, again suggesting that the E1506D and E1506G mutations may impair surface expression in the homomeric state. Login to comment
204 The off-rate of MgADP was not significantly different for the G334D/E1506K channels but was slower for the G334D/E1506D and G334D/E1506G channels, with a toff of 10 and 11 s, respectively. Login to comment
205 The off-rate of MgATP was significantly less for all three mutant channels, with a toff of 8.5 s for G334D/E1506K, 16 s for G334D/E1506G, and 67 s for G334D/E1506D. Login to comment
210 Such ATP preconditioning reduced the ATP sensitivity of the two neonatal diabetic mutant channels but had little or no effect on wild-type or E1506K channels, respectively (Table 1). Login to comment
211 As a consequence, the IC50 for the ATP block of the homomeric and heterozygous E1506D and E1506G channels was significantly greater than wild-type, whereas that of hetE1506K was no different, and that of homE1506K was actually slightly smaller (Fig. 6, Table 1). Login to comment
213 Preconditioning pulses of .300 mmol/L MgATP markedly reduced the ability of 100 mmol/L MgATP to block E1506D and E1506G channels but had only a small effect on wild-type channels and no effect on the homE1506K channels. Login to comment
265 The off-rate of MgADP was much faster than that of MgATP for the E1506D channels, and MgADP had little stimulatory effect, which supports arguments that it cannot be the MgADP-bound state. Login to comment
266 The most striking difference between the E1506K and E1506G/E1506D channels is that shown in Figs. 6 and 7: pre-exposure to millimolar concentrations of MgATP desensitizes the channel to subsequent inhibition by a lower ATP concentration. Login to comment
95 A small but significant increase in resting current was observed for both homomeric Kir6.2/SUR1-E1506D (homE1506D) and Kir6.2/SUR1-E1506G (homE1506G) channels (Fig. 1). Login to comment
110 This suggests that the neonatal diabetes mutations have little (E1506D) or no (E1506G) effect on expression levels of the KATP channel in the heterozygous state. Login to comment
178 No increase in current was observed for the Kir6.2-G334D/SUR1-E1506D (G334D/E1506D) or Kir6.2-G334D/SUR1-E1506G (G334D/ E1506G) channels; in contrast, the Kir6.2-G334D/SUR1-E1506K (G334D/E1506K) currents increased 1.5-fold on excision. Login to comment
203 The off-rate of MgADP was not significantly different for the G334D/E1506K channels but was slower for the G334D/E1506D and G334D/E1506G channels, with a toff of 10 and 11 s, respectively. Login to comment
212 Preconditioning pulses of .300 mmol/L MgATP markedly reduced the ability of 100 mmol/L MgATP to block E1506D and E1506G channels but had only a small effect on wild-type channels and no effect on the homE1506K channels. Login to comment