ATP-sensitive

The absorption of sulfonylureas from the upper gastrointestinal tract is faidy rapid and complete. The agents are transported in the blood as protein-bound complexes. As they are released from protein-binding sites, the free (unbound) form becomes available for diffusion into tissues and to sites of action. Specific receptors are present on pancreatic islet P-ceU surfaces which bind sulfonylureas with high affinity. Binding of sulfonylureas to these receptors appears to be coupled to an ATP-sensitive channel to stimulate insulin secretion. These agents may also potentiate insulin-stimulated glucose transport in adipose tissue and skeletal muscle. 

Antidiabetic Drugs other than Insulin. Figure 1 Sulphonylureas stimulate insulin release by pancreatic (3-cells. They bind to the sulphonylurea receptor (SUR-1), which closes Kir6.2 (ATP-sensitive) potassium channels. This promotes depolarisation, voltage-dependent calcium influx, and activation of calcium-sensitive proteins that control exocytotic release of insulin. 

ATP-sensitive K+ channel ATP-regulated K+ channel Kaxp channel SURx/Kir6.x channel... 

Here, one mutated subunit is sufficient to strongly reduce ATP sensitivity thereby inducing additional symptoms in extrapancreatic tissues. To date two mutants within SlIRl are known (11424V and HI 023Y), resulting in hyperactive channels and PNDM. 

Schwanstecher C, Schwanstecher M (2002) Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2 diabetes. Diabetes 51 (Suppl 3) S358-362... 

Ashcroft FM (2005) ATP-sensitive potassium channelo-pathies focus on insulin secretion. J Clin Invest 115 2047-2055... 

Persistant hyperinsulinemic hypoglycemia of infancy (PHHI) SUR1 subunits of ATP-sensitive potassium channels (KATP) Sulfonylurea... 

Labelling Na,K-ATPase with ATP analogues provides evidence for contribution from charged residues that are widely separated in the sequence of a subunit of Na,K-ATPase. The first indication came from ATP sensitive covalent insertion of fluorescein-isothiocyanate (FITC) into Lys ° in the a subunit [90], The strong fluorescence signal provides a convenient probe for monitoring conformational transitions in the proteins. Site-directed mutagenesis of Lys reduces the activity of... 

There are several major classes of Ca channels (1) receptor-operated Ca channels in plasma membranes (2) ligand-gated Ca " channels in intracellular membranes and (3) voltage-dependent Ca channels that are usually found in plasma membranes or the invaginations of the plasma membrane that are known as transverse tubule membranes. Receptor-dependent or receptor-operated Ca channels (ROCCs) are primarily opened in response to activation of their associated receptors and, by definition, exhibit a certain amount of selectivity for Ca " over other cations. Several potentially different types of ROCCs have been characterized including ATP-sensitive channels in smooth muscle [1], mitogen and IP3-sensitive... 

While producing the same effect as sulfonylureas, nonsulfonylurea secretagogues, also referred to as meglitinides, have a much shorter onset and duration of action. Nonsulfonylurea secretagogues also produce a pharmacologic effect by interacting with ATP-sensitive potassium channels on the (1-cells however, this binding is to a receptor adjacent to those to which sulfonylureas bind. 

A benzopyran derivative, RP-58866 (70) is under development by Rhone-Poulenc. Patch clamp studies in guinea-pig ventricular myocytes indicate that RP-58866 inhibits the inward rectifying potassium current (7ki) with no effects on the delayed rectifier, ATP-sensitive potassium currents or calcium currents [200]. RP-58866 increases APD90 of Purkinje fibres by about 45% at 0.3 yuM without affecting K ax [201]. The compound was effective... 

Abndnla R, Matchkov W, Jeppesen PB, Nilsson H, AaUejaer C, Hermansen K. (2008) Rebandioside A directly stimnlates insulin secretion from pancreatic beta cells A glucose-dependent action via inhibition of ATP-sensitive K-channels. Diabetes ObesMetab 10 1074-1085. 

Tang and colleagues proposed that HA increases ATP-sensitive K+ channel currents, which may underlie the observed HA vasorelaxation, and suggested that enhanced production of free radicals is involved in this physiological response. These results are consistent with the observations of Huang, who suggested that HA-induced relaxation of... 

Fast Inward Sodium Current L Type Calcium Current Transient Outward Current Sodium-Calcium Exchange Current ATP Sensitive Potassium Current Inward Rectifying Potassium Current Delayed Rectifying Potassium Current... 

The sulfonylurea receptor was identified as an adenosine triphosphate (ATP) sensitive potassium (Katp) channel that is present on the (3-cell membrane surface. Closure of these K tp channels causes (3-cell membrane... 

Miki TK et al. The structure and function of the ATP-sensitive K+ channel in insulin-secreting pancreatic beta-cells. J Molec Endocrinol 1999 22 113-123. 

Glucotrol (Glipizide) 10.7 (0.5) 14.1 (0.5) 13.1 (0.6) A second generation sulfonylurea that blocks ATP-sensitive K-channels in the membrane of beta cells, stimulating the release of insulin. 

Akasaka T, KUnedinst S, Ocorr K, Bustamante EL, Kim SK, Bodmer R. (2006) The ATP-sensitive potassiiun (KATP) channel-encoded dSUR gene is required for Drosophila heart function and is regulated by tinman. Proc Natl AcadSci USA 103, 11999-2004. 

Gross GJ, Fryer RM. (1999) Sarcolemmal versus mitochondrial ATP-sensitive K channels and myocardial preconditioning. Circ Res 84, 973-9. 

---