Running out of time: the decline of channel activity and nucleotide activation in ATP-sensitive K-channels

Journal article

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. de-/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 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.

Authors: Proks, P; Puljung, M; Vedovato, N; Sachse, G; Mulvaney, R

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Royal Society
• Journal: Philosophical Transactions of the Royal Society of London: Biological Sciences
• Volume: 371
• Issue: 1700
• Pages: 20150426
• Publication date: 2016-07-04
• Acceptance date: 2016-04-17
• DOI: 10.1098/rstb.2015.0426
• EISSN: 1471-2970
• ISSN: 0962-8436
• Keywords: KATP channel; MgADP activation; rundown