M-LDH serves as a sarcolemmal K(ATP) channel subunit essential for cell protection against ischemia.
ATP-sensitive K(+) (K(ATP)) channels in the heart are normally closed by high intracellular ATP, but are activated during ischemia to promote cellular survival. These channels are heteromultimers composed of Kir6.2 subunit, an inwardly rectifying K(+) channel core, and SUR2A, a regulatory subunit implicated in ligand-dependent regulation of channel gating. Here, we have shown that the muscle form (M-LDH), but not heart form (H-LDH), of lactate dehydrogenase is directly physically associated with the sarcolemmal K(ATP) channel by interacting with the Kir6.2 subunit via its N-terminus and with the SUR2A subunit via its C-terminus. The species of LDH bound to the channel regulated the channel activity despite millimolar concentration of intracellular ATP. The presence of M-LDH in the channel protein complex was required for opening of K(ATP) channels during ischemia and ischemia-resistant cellular phenotype. We conclude that M-LDH is an integral part of the sarcolemmal K(ATP) channel protein complex in vivo, where, by virtue of its catalytic activity, it couples the metabolic status of the cell with the K(ATP) channels activity that is essential for cell protection against ischemia.
Crawford
Russell M
RM
Tayside Institute of Child Health, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.
Budas
Grant R
GR
Jovanović
Sofija
S
Ranki
Harri J
HJ
Wilson
Timothy J
TJ
Davies
Anthony M
AM
Jovanović
Aleksandar
A
D000230:Adenocarcinoma / Q000473:pathology; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D015687:Cell Hypoxia; D003402:Creatine Kinase / Q000737:chemistry / Q000502:physiology; D052283:Creatine Kinase, MM Form; D006168:Guinea Pigs; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D007511:Ischemia / Q000378:metabolism*; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000080864:Lactate Dehydrogenase 5; D046911:Macromolecular Substances; D051379:Mice; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000502:physiology*; D025941:Protein Interaction Mapping; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012508:Sarcolemma / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; D046911:Macromolecular Substances; D009124:Muscle Proteins; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; C409667:lactate dehydrogenase 1; D003402:Creatine Kinase; D052283:Creatine Kinase, MM Form; D011188:Potassium