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ATP-sensitive K-channels and insulin secretion in health and disease

Friday 28th September 2001 - 09:00 to 10:00
INI Seminar Room 1
Session Title: 
Vertical Integration in Biology: From Molecules to Organisms
ATP sensitive K-channels (ATP channels) play important roles in a diverse range of tissues (including pancreatic beta-cells, neurones, and cardiac, skeletal and smooth muscles) by coupling the metabolic state of the cell to its electrical activity. In pancreatic beta-cells, for example, K ATP closure in response to glucose metabolism produces membrane depolarization, leading to Ca 2+ influx and insulin secretion. K ATP channels are also involved in glucose sensing in hypothalamic neurones, in ischemic preconditioning of cardiac muscle and, in vascular smooth muscle, in the regulation of vessel tone. Metabolic regulation is mediated by changes in intracellular ATP (which blocks the channel) and MgADP (which activates the channel). K ATP channels are inhibited by sulphonylurea drugs, which stimulate insulin secretion and are used to treat type 2 diabetes, and activated by K ATP-channel openers, a structurally diverse group of drugs with a wide range of potential therapeutic applications.

K ATP channels share a common pore-forming subunit, Kir6.2, which associates in a 4:4 heteromeric complex with different sulphonylurea receptor isoforms (SUR1 in beta-cells, SUR2A in heart, and SUR2B in smooth muscle). Kir6.2 serves as an ATP-sensitive pore while SUR acts as a regulatory subunit, endowing the channel with sensitivity to the stimulatory effects of MgADP and K ATP-channel openers and the inhibitory action of sulphonylureas. K ATP channels containing different types of SUR subunit show different sensitivities to sulphonylureas and K ATP-channel openers. Mutations in SUR1 or Kir6.2 that result in channel closure produce congenital hypoglycaemia of infancy in man, a disease of excessive insulin secretion. Conversely, impaired cell metabolism, or mutations in Kir6.2, which lead to enhanced channel activity, result in diabetes.

This talk will present an overview of our currents studies on the relationship between K ATP-channel structure and function, focusing on three main topics: inhibition by ATP; activation by Mg-nucleotides such as MgADP and MgATP; and the role of K ATP channels in disease.

University of Cambridge Research Councils UK
    Clay Mathematics Institute London Mathematical Society NM Rothschild and Sons