Molecular mechanisms of action of glyburide on the beta cell

https://doi.org/10.1016/0002-9343(90)90330-GGet rights and content

Abstract

A high-affinity sulfonylurea receptor has been identified on the plasma membrane of the beta cell. The potent second-generation sulfonylureas, glyburide and glipizide, saturate the receptor in the low nM concentration range, whereas first-generation drugs bind to and saturate the receptor in the μM range. For each of the sulfonyl-ureas, there is excellent quantitative agreement among the equilibrium binding constant (Kd), the half-maximal inhibition of potassium ion (K+) efflux (K0.5), and the half-maximal stimulation of insulin secretion (ED50), when these values are obtained from insulin-secreting cell lines or from isolated mouse pancreatic islets. The inhibition of K+ efflux by the sulfonylureas, coupled with the sulfonylurea inhibition of the activity of a specific adenosine triphosphate (ATP)-sensitive K+ channel embedded in the plasma membrane of whole cells or in excised membrane patches, suggests that the sulfonylurea receptor is this channel protein or a closely associated subunit. The activity of the ATP-sensitive K+ channel is also controlled by the insulin secretagogues, glucose and certain amino acids. These compounds must be metabolized to inhibit the channel activity and appear to do so by increasing the level of ATP or by increasing the ATP/adenosine diphosphate (ADP) ratio. ATP reduces channel activity by binding to a specific nucleotide-binding site on the cytoplasmic surface of the protein. There is a synergy between the action of glucose and that of the sulfonylureas. The sulfonylureas, for example, are better effectors of insulin secretion in the presence of glucose. Inhibition of the ATP-sensitive K+ channels results in depolarization of the plasma membrane and a subsequent influx of extracellular calcium ions through voltage-dependent calcium channels. An increase in the free intracellular calcium level is the signal, or “second messenger,” that triggers exocytosis and the release of insulin. The sulfonylurea receptor has a molecular weight of 140,000 and can be solubilized by digitonin, retaining the same rank order of sulfonylurea binding affinities as the membrane-bound protein. Several laboratories are currently purifying the receptor and/or cloning the receptor gene.

References (36)

  • H Schmidt-Antomarchi et al.

    The receptor for the antidiabetic sulfonylureas controls the activity of the ATP-modulated K+ channel

    J Biol Chem

    (1987)
  • AE Boyd

    Sulfonylurea receptors, ion channels, and fruit flies

    Diabetes

    (1988)
  • AS Rajan et al.

    Ion channels and insulin secretion

    Diabetes Care

    (1990)
  • JC Henquin

    D-glucose inhibits potassium efflux from pancreatic islets cells

    Nature (Lond)

    (1978)
  • DL Cook et al.

    Intracellular ATP directly blocks K+ channels in pancreatic β-cells

    Nature (Lond)

    (1984)
  • F Ashcroft et al.

    Glucose induces closure of single potassium channels in isolated rat pancreatic β-cells

    Nature (Lond)

    (1984)
  • P Rorsman et al.

    Glucose-dependent K+ channels in pancreatic β-cells are regulated by intracellular ATP

    Pfluegers Arch

    (1985)
  • I Findlay et al.

    Quinine inhibits Ca2+-independent K+ channels whereas tetraethylammonium inhibits Ca2+ activated K+ channels in insulin-secreting cells

    FEBS Lett

    (1986)
  • Cited by (0)

    This work was supported by United States Public Health Service Grants DK 34447, DK 27635 (Diabetes and Endocrinology Research Center), and DK 41898 (RR00350), funds from the Methodist Research Foundation, grants from the Biomedical Research Foundation and the American Diabetes Association to Daniel A. Nelson, and a Postdoctoral Fellowship from the Juvenile Diabetes Foundation to Lydia Aguilar-Bryan.

    View full text