Molecular biology of K(ATP) channels and implications for health and disease

Abstract

The ATP-sensitive potassium (K(ATP)) channel is expressed in most excitable tissues and plays a critical role in numerous physiological processes by coupling intracellular energetics to electrical activity. The channel is comprised of four Kir6.x subunits associated with four regulatory sulfonylurea receptors (SUR). Intracellular ATP acts on Kir6.x to inhibit channel activity, while MgADP stimulates channel activity through SUR. Changes in the cytosolic [ATP] to [ADP] ratio thus determine channel activity. Multiple mutations in Kir6.x and SUR genes have implicated K(ATP) channels in various diseases ranging from diabetes and hyperinsulinism to cardiac arrhythmias and cardiovascular disease. Continuing studies of channel physiology and pathology will bring new insights to the molecular basis of K(ATP) channel function, leading to a better understanding of the role that K(ATP) channels play in both health and disease.

Figure 1

Membrane topology of Kir6.x and SURx and K_ATP channel assembly. A: Kir6 subunits consist of two transmembrane helices (M1 and M2) connected by a ‘P-loop’ which defines the selectivity filter of the channel. SUR is composed of two six-helix transmembrane domains (TMD1 and TMD2), each followed by a nucleotide binding fold (NBF1 and 2). TMD0 interacts directly with Kir6 to translate agonist and antagonist binding events to a gating signal. B: Four Kir6 subunits tetramerize to form the channel pore and each Kir6 subunit is associated with one SUR subunit.

Figure 2

Relationship between channel open probability (Po) and K_1/2,ATP and kinetic model for channel gating. A: As the channel Po increases, by increasing membrane PIP₂ or with open state stabilizing mutations, the K_1/2,ATP also increases reproducibly along this characteristic curve. B: The Po-K_1/2,ATP relationship can be modeled by a kinetic scheme in which both the open state and an ATP-dependent closed state sprout from a middle, ATP-independent, closed state (see text for elaboration).

Figure 3

The glucose stimulated insulin secretion (GSIS) pathway in the pancreatic β-cell. An increase in the intracellular ratio of [ATP] to [ADP] will inhibit K_ATP channels, leading to membrane depolarization. The increase in membrane potential activates voltage dependent calcium channels (VDCC) and the resulting influx of Ca²⁺ triggers insulin secretion. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]