Reversal of the ATP-liganded state of ATP-sensitive K+ channels by adenylate kinase activity.
The mechanism that promotes transition from the ATP- to the ADP-liganded state of ATP-sensitive K+ (KATP) channels and consequent channel opening in a cytosolic environment of high ATP concentration has yet to be understood. A mechanism examined here that could reverse the ATP-inhibited state is based on the action of adenylate kinase to catalyze phosphoryl transfer between ATP and AMP, resulting in transformation of ATP into ADP. In membrane patches excised from guinea pig cardiomyocytes, AMP alone did not affect channel behavior but increased the open probability of ATP-inhibited KATP channels. This required MgCl2 and a hydrolyzable form of ATP and was prevented by P1,P5-di-adenosine-5'-pentaphosphate, an inhibitor of adenylate kinase. The single channel amplitude and kinetics of channel openings induced by the ADP-generating substrates of adenylate kinase, AMP and MgATP, were indistinguishable from the biophysical properties of the KATP channel exhibited after addition of MgADP. In whole cell voltage-clamped cardiomyocytes, introduction of exogenous adenylate kinase along with millimolar MgATP and AMP induced a K+ current that was suppressed by a sulfonylurea blocker of KATP channels. Enriched sarcolemmal membrane preparations were found to possess ATP.AMP phosphotransferase activity with properties attributable to an extramitochondrial isoform of adenylate kinase. These results indicate that adenylate kinase is a naturally occurring component of sarcolemmal membranes that could provide dynamic governance of KATP channel opening through its phosphoryl transfer catalytic action in the microenvironment of the channel.
Elvir-Mairena
J R
JR
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905, USA. terzic.andre@mayo.edu
Jovanovic
A
A
Gomez
L A
LA
Alekseev
A E
AE
Terzic
A
A
D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism
D015221:Potassium Channels; D009243:NAD; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000263:Adenylate Kinase; D005905:Glyburide