title: Running out of time: the decline of channel activity and nucleotide activation in adenosine triphosphate-sensitive K-channels.
abstract: KATP channels act as key regulators of electrical excitability by coupling metabolic cues-mainly intracellular adenine nucleotide concentrations-to cellular potassium ion efflux. However, their study has been hindered by their rapid loss of activity in excised membrane patches (rundown), and by a second phenomenon, the decline of activation by Mg-nucleotides (DAMN). Degradation of PI(4,5)P2 and other phosphoinositides is the strongest candidate for the molecular cause of rundown. Broad evidence indicates that most other determinants of rundown (e.g. phosphorylation, intracellular calcium, channel mutations that affect rundown) also act by influencing KATP channel regulation by phosphoinositides. Unfortunately, experimental conditions that reproducibly prevent rundown have remained elusive, necessitating post hoc data compensation. Rundown is clearly distinct from DAMN. While the former is associated with pore-forming Kir6.2 subunits, DAMN is generally a slower process involving the regulatory sulfonylurea receptor (SUR) subunits. We speculate that it arises when SUR subunits enter non-physiological conformational states associated with the loss of SUR nucleotide-binding domain dimerization following prolonged exposure to nucleotide-free conditions. This review presents new information on both rundown and DAMN, summarizes our current understanding of these processes and considers their physiological roles.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Proks
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Puljung
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Natascia
authors.initials: N
authors.lastname: Vedovato
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Gregor
authors.initials: G
authors.lastname: Sachse
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Mulvaney
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK frances.ashcroft@dpag.ox.ac.uk.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
mesh_terms: D000818:Animals; D001692:Biological Transport; D054086:KATP Channels / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism*
chemical_list: D054086:KATP Channels; D009711:Nucleotides
keywords: KATP channel; MgADP activation; rundown