Running out of time: the decline of channel activity and nucleotide activation in ATP-sensitive K-channels
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...
| Main Authors: | , , , , , |
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| Format: | Journal article |
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Royal Society
2016
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| _version_ | 1826300896878788608 |
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| author | Proks, P Puljung, M Vedovato, N Sachse, G Mulvaney, R Ashcroft, F |
| author_facet | Proks, P Puljung, M Vedovato, N Sachse, G Mulvaney, R Ashcroft, F |
| author_sort | Proks, P |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T05:24:07Z |
| format | Journal article |
| id | oxford-uuid:dff61185-85e5-4441-b27c-9bcbe309bb92 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T05:24:07Z |
| publishDate | 2016 |
| publisher | Royal Society |
| record_format | dspace |
| spelling | oxford-uuid:dff61185-85e5-4441-b27c-9bcbe309bb922022-03-27T09:43:12ZRunning out of time: the decline of channel activity and nucleotide activation in ATP-sensitive K-channelsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:dff61185-85e5-4441-b27c-9bcbe309bb92Symplectic Elements at OxfordRoyal Society2016Proks, PPuljung, MVedovato, NSachse, GMulvaney, RAshcroft, FKATP 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. |
| spellingShingle | Proks, P Puljung, M Vedovato, N Sachse, G Mulvaney, R Ashcroft, F Running out of time: the decline of channel activity and nucleotide activation in ATP-sensitive K-channels |
| title | Running out of time: the decline of channel activity and nucleotide activation in ATP-sensitive K-channels |
| title_full | Running out of time: the decline of channel activity and nucleotide activation in ATP-sensitive K-channels |
| title_fullStr | Running out of time: the decline of channel activity and nucleotide activation in ATP-sensitive K-channels |
| title_full_unstemmed | Running out of time: the decline of channel activity and nucleotide activation in ATP-sensitive K-channels |
| title_short | Running out of time: the decline of channel activity and nucleotide activation in ATP-sensitive K-channels |
| title_sort | running out of time the decline of channel activity and nucleotide activation in atp sensitive k channels |
| work_keys_str_mv | AT proksp runningoutoftimethedeclineofchannelactivityandnucleotideactivationinatpsensitivekchannels AT puljungm runningoutoftimethedeclineofchannelactivityandnucleotideactivationinatpsensitivekchannels AT vedovaton runningoutoftimethedeclineofchannelactivityandnucleotideactivationinatpsensitivekchannels AT sachseg runningoutoftimethedeclineofchannelactivityandnucleotideactivationinatpsensitivekchannels AT mulvaneyr runningoutoftimethedeclineofchannelactivityandnucleotideactivationinatpsensitivekchannels AT ashcroftf runningoutoftimethedeclineofchannelactivityandnucleotideactivationinatpsensitivekchannels |