Author:
Proks Peter,Puljung Michael C.,Vedovato Natascia,Sachse Gregor,Mulvaney Rachel,Ashcroft Frances M.
Abstract
K
ATP
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
d
ecline of
a
ctivation by
M
g-
n
ucleotides (DAMN). Degradation of PI(4,5)P
2
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 K
ATP
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’.
Funder
Wellcome Trust
Sixth Framework Programme
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology
Cited by
15 articles.
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