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Sulfonylureas suppress the stimulatory action of Mg-nucleotides on Kir6.2/SUR1 but not Kir6.2/SUR2A KATP channels: A mechanistic study
- Source :
- The Journal of General Physiology
- Publication Year :
- 2014
- Publisher :
- The Rockefeller University Press, 2014.
-
Abstract
- Sulfonylureas suppress the stimulatory effect of Mg-nucleotides on recombinant β-cell (Kir6.2/SUR1) but not cardiac (Kir6.2/SUR2A) KATP channels.<br />Sulfonylureas, which stimulate insulin secretion from pancreatic β-cells, are widely used to treat both type 2 diabetes and neonatal diabetes. These drugs mediate their effects by binding to the sulfonylurea receptor subunit (SUR) of the ATP-sensitive K+ (KATP) channel and inducing channel closure. The mechanism of channel inhibition is unusually complex. First, sulfonylureas act as partial antagonists of channel activity, and second, their effect is modulated by MgADP. We analyzed the molecular basis of the interactions between the sulfonylurea gliclazide and Mg-nucleotides on β-cell and cardiac types of KATP channel (Kir6.2/SUR1 and Kir6.2/SUR2A, respectively) heterologously expressed in Xenopus laevis oocytes. The SUR2A-Y1206S mutation was used to confer gliclazide sensitivity on SUR2A. We found that both MgATP and MgADP increased gliclazide inhibition of Kir6.2/SUR1 channels and reduced inhibition of Kir6.2/SUR2A-Y1206S. The latter effect can be attributed to stabilization of the cardiac channel open state by Mg-nucleotides. Using a Kir6.2 mutation that renders the KATP channel insensitive to nucleotide inhibition (Kir6.2-G334D), we showed that gliclazide abolishes the stimulatory effects of MgADP and MgATP on β-cell KATP channels. Detailed analysis suggests that the drug both reduces nucleotide binding to SUR1 and impairs the efficacy with which nucleotide binding is translated into pore opening. Mutation of one (or both) of the Walker A lysines in the catalytic site of the nucleotide-binding domains of SUR1 may have a similar effect to gliclazide on MgADP binding and transduction, but it does not appear to impair MgATP binding. Our results have implications for the therapeutic use of sulfonylureas.
- Subjects :
- medicine.medical_specialty
endocrine system
Physiology
medicine.drug_class
Xenopus
Amino Acid Motifs
Molecular Sequence Data
Plasma protein binding
Pharmacology
Biology
Sulfonylurea Receptors
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Adenosine Triphosphate
Internal medicine
Insulin-Secreting Cells
medicine
Animals
Humans
Gliclazide
Amino Acid Sequence
Binding site
Potassium Channels, Inwardly Rectifying
Research Articles
Cells, Cultured
030304 developmental biology
0303 health sciences
Binding Sites
Kir6.2
Sulfonylurea
3. Good health
Rats
Adenosine Diphosphate
Adenosine diphosphate
Endocrinology
chemistry
cardiovascular system
Sulfonylurea receptor
Adenosine triphosphate
Ion Channel Gating
030217 neurology & neurosurgery
hormones, hormone substitutes, and hormone antagonists
medicine.drug
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 15407748 and 00221295
- Volume :
- 144
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- The Journal of General Physiology
- Accession number :
- edsair.doi.dedup.....4e32b784eebfd3ab7e0c3d3fdb9385d1