ABCMdb

PMID: 20033705

Olson TM, Terzic A
Human K(ATP) channelopathies: diseases of metabolic homeostasis.
Pflugers Arch. 2010 Jul;460(2):295-306. Epub 2009 Dec 24., [PubMed]

Sentences

No. Mutations Sentence Comment

139 ABCC9 p.Thr1547Ile Identified in exon 38, specific for the cardiac splice variant of SUR2A, this heterozygous c.4640C>T transition caused substitution of the threonine residue at amino acid position 1547 with isoleucine (T1547I). Login to comment 141 ABCC9 p.Thr1547Ile Identified in exon 38, specific for the cardiac splice variant of SUR2A, this heterozygous c.4640C>T transition caused substitution of the threonine residue at amino acid position 1547 with isoleucine (T1547I). Login to comment 143 ABCC9 p.Thr1547Ile Patch-clamp recording demonstrated that the T1547I substitution compromised adenine nucleotide-dependent induction of KATP channel current [89]. Login to comment 144 ABCC9 p.Thr1547Ile Mutant T1547I SUR2A, coexpressed with the KCNJ11-encoded Kir6.2 pore, generated an aberrant channel that retained ATP-induced inhibition of potassium current but demonstrated a blunted response to ADP. Login to comment 145 ABCC9 p.Thr1547Ile ABCC9 p.Thr1547Ile A deficit in nucleotide gating, resulting from the T1547I mutation, would compromise the homeostatic role of the KATP channel required for proper readout of cellular distress and maintenance of electrical stability. Login to comment 146 ABCC9 p.Thr1547Ile Mutant T1547I SUR2A, coexpressed with the KCNJ11-encoded Kir6.2 pore, generated an aberrant channel that retained ATP-induced inhibition of potassium current but demonstrated a blunted response to ADP. Login to comment 147 ABCC9 p.Thr1547Ile A deficit in nucleotide gating, resulting from the T1547I mutation, would compromise the homeostatic role of the KATP channel required for proper readout of cellular distress and maintenance of electrical stability. Login to comment 168 ABCC9 p.Ala1513Thr Another mutated allele harbored a missense mutation (c.4537G>A) causing the amino acid substitution A1513T. Login to comment 170 ABCC9 p.Ala1513Thr Another mutated allele harbored a missense mutation (c.4537G>A) causing the amino acid substitution A1513T. Login to comment 173 ABCC9 p.Ala1513Thr Indeed, ATP-induced KATP channel gating was aberrant in channel mutants, suggesting that structural alterations induced by the mutations A1513T and Fs1524 of SUR2A distorted ATP-dependent pore regulation [17]. Login to comment 174 ABCC9 p.Ala1513Thr Thus, the mutations A1513T and Fs1524 compromise ATP hydrolysis at SUR2A NBD2, generating distinct reaction kinetic defects. Login to comment 175 ABCC9 p.Ala1513Thr ABCC9 p.Ala1513Thr Aberrant catalytic properties in the A1513T and Fs1524 mutants translated into abnormal interconversion of discrete conformations in the NBD2 ATPase cycle. Login to comment 176 ABCC9 p.Ala1513Thr ABCC9 p.Ala1513Thr Alterations in hydrolysis-driven SUR2A conformational probability induced by A1513T and Fs1524 perturbed intrinsic catalytic properties of the SUR2A ATPase, compromising proper translation of cellular energetic signals into KATP channel-mediated membrane electrical events. Login to comment 177 ABCC9 p.Ala1513Thr Aberrant catalytic properties in the A1513T and Fs1524 mutants translated into abnormal interconversion of discrete conformations in the NBD2 ATPase cycle. Login to comment 178 ABCC9 p.Ala1513Thr Alterations in hydrolysis-driven SUR2A conformational probability induced by A1513T and Fs1524 perturbed intrinsic catalytic properties of the SUR2A ATPase, compromising proper translation of cellular energetic signals into KATP channel-mediated membrane electrical events. Login to comment