Molecular biology of adenosine triphosphate-sensitive potassium channels

K(ATP) channels are a newly defined class of potassium channels based on the physical association of an ABC protein, the sulfonylurea receptor, and a K+ inward rectifier subunit. The β-cell K(ATP) channel is composed of SUR1, the high-affinity sulfonylurea receptor with multiple TMDs and two NBFs, and K(IR)6.2, a weak inward rectifier, in a 1:1 stoichiometry. The pore of the channel is formed by K(IR)6.2 in a tetrameric arrangement; the overall stoichiometry of active channels is (SUR1/K(IR)6.2)4. The two subunits form a tightly integrated whole. K(IR)6.2 can be expressed in the plasma membrane either by deletion of an ER retention signal at its C-terminal end or by high-level expression to overwhelm the retention mechanism. The single- channel conductance of the homomeric K(IR)6.2 channels is equivalent to SUR/K(IR)6.2 channels, but they differ in all other respects, including bursting behavior, pharmacological properties, sensitivity to ATP and ADP, and trafficking to the plasma membrane. Coexpression with SUR restores the normal channel properties. The key role K(ATP) channels play in the regulation of insulin secretion in response to changes in glucose metabolism is underscored by the finding that a recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is caused by mutations in K(ATP) channel subunits that result in the loss of channel activity. K(ATP) channels set the resting membrane potential of β-cells, and their loss results in a constitutive depolarization that allows voltage-gated Ca2+ channels to open spontaneously, increasing the cytosolic Ca2+ levels enough to trigger continuous release of insulin. The loss of K(ATP) channels, in effect, uncouples the electrical activity of β-cells from their metabolic activity. PHHI mutations have been informative on the function of SUR1 and regulation of K(ATP) channels by adenine nucleotides. The results indicate that SUR1 is important in sensing nucleotide changes, as implied by its sequence similarity to other ABC proteins, in addition to being the drug sensor. An unexpected finding is that the inhibitory action of ATP appears to be through a site located on K(IR)6.2, whose affinity for ATP is modified by SUR1. A PHHI mutation, G1479R, in the second NBF of SUR1 forms active K(ATP) channels that respond normally to ATP, but fail to activate with MgADP. The result implies that ATP tonically inhibits K(ATP) channels, but that the ADP level in a fasting β-cell antagonizes this inhibition. Decreases in the ADP level as glucose is metabolized result in K(ATP) channel closure. Although K(ATP) channels are the target for sulfonylureas used in the treatment of NIDDM, the available data suggest that the identified K(ATP) channel mutations do not play a major role in diabetes. Understanding how K(ATP) channels fit into the overall scheme of glucose homeostasis, on the other hand, promises insight into diabetes and other disorders of glucose metabolism, while understanding the structure and regulation of these channels offers potential for development of novel compounds to regulate cellular electrical activity.