K(ATP) channels "vingt ans après": ATG to PDB to Mechanism.
A multidisciplinary effort over twenty years has provided deep insight into the nature of K(ATP) channels. First discovered in cardiomyocytes and pancreatic beta-cells, as ubiquitous sensors of the ADP/ATP ratio they are implicated in multiple disorders characterized by the uncoupling of excitation from metabolism. Composed of two disparate subunits these large octameric channels present a formidable challenge to scientists interested in understanding mechanism in physical, chemical, and structural terms. Post-cloning studies have defined the domains and interactions, within and between the nucleotide-inhibited K(IR) pore and nucleotide-stimulated, drug-binding core of the ATP-Binding Cassette (ABC) regulatory subunits, that control channel assembly and gating. Determination of the three-dimensional structures of the bacterial prototypes of the channel subunits allowed homology modeling and has provided increasingly detailed mechanistic understanding. Here I review the early electrophysiology and molecular biology of K(ATP) channels, cover biophysical principles governing their single channel kinetics, integrate this with current efforts to understand ligand-recognition and gating within the pore and SUR core, and propose a mechanism of coupling based on recent identification of a SUR gatekeeper module and first composite models of (SUR/K(IR) 6.0)(4) complexes. This mechanism, based on interactions between inter-K(IR) subunit ATP-binding pockets and a unique bi-directional regulatory apparatus comprised of elements from the gatekeeper and K(IR) amino terminus, provides a molecular perspective for understanding the biophysical basis underlying the polar effects of pathogenic mutations in K(ATP) channel subunits.
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. ababenko@bcm.tmc.edu
Andrey P
AP
Babenko
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D030562:Databases, Protein; D006801:Humans; D054086:KATP Channels; D008958:Models, Molecular; D008969:Molecular Sequence Data; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D011487:Protein Conformation; D021122:Protein Subunits; D011955:Receptors, Drug / Q000737:chemistry / Q000378:metabolism; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D054086:KATP Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C092520:uK-ATP-1 potassium channel