ION CHANNELS

Insulin secretion by the pancreatic Beta cell is dependent upon transmembrane ion fluxes gated by the ATP-regulated potassium channel and the voltage regulated, L-type calcium channel. This work group examined major recent advances in the structure and modulation of ion channels and how those advances may pertain to the physiology of insulin secretion and the pharmacological treatment of Type 2 (non-insulin-dependent) diabetes mellitus. Structural studies have revealed that voltage gated ion channels are related, complex, and comprised of multiple components: sodium channels consist of three distinct subunits. L-type calcium channels, crucial to the insulin secretory response are structurally related to the sodium channel but contain additional subunits. Potassium channels are less closely related and appear to function as homotetramers. Modulation of ion channel activity is similarly complex: site specific phosphorylation by multiple protein kinases under the control of several intracellular second messenger systems may increase or decrease conductance. Subunit composition and relatively stable changes in the modal state of ion channels also appear to be critical to ion channel gating properties. Functional studies of the Beta-cell ATP-regulated potassium channel suggest two distinct nucleotide binding sites which link this channel to the metabolic state of the Beta cell. The multiple paths of ion channel modulation provide multiple targets for therapeutic intervention. Where detailed characterisation of ion channel structure has been achieved, those targets are being used for specific drug design. Such complete characterisation has not yet been achieved for Beta-cell ion channels and this presents a major goal for diabetes research.