Glycolytic pathway intermediates activate cardiac ryanodine receptors

Area of Science:

• Biochemistry
• Cardiology
• Molecular Biology

Background:

• Myocardial ischemia and reperfusion increase glycolytic activity, potentially altering levels of glycolytic intermediates.
• Cardiac ryanodine receptors (RyR) play a critical role in calcium release from the sarcoplasmic reticulum (SR).

Purpose of the Study:

• To investigate the effect of sugar phosphate intermediates of glycolysis on cardiac ryanodine receptor (RyR) channel activity.
• To determine if glycolytic flux changes can modulate sarcoplasmic reticulum (SR) calcium release through RyR channels.

Main Methods:

• Incorporation of sheep cardiac ryanodine receptor (RyR) channels into bilayers.
• Measurement of channel open probability (Po) and [3H]ryanodine binding to isolated cardiac sarcoplasmic reticulum (SR) membrane vesicles.
• Testing the effects of various sugar phosphates, including fructose-1,6-diphosphate (FDP), glucose-1-phosphate (G-1-P), fructose-6-phosphate (F-6-P), and glucose-6-phosphate (G-6-P).

Main Results:

• Fructose-1,6-diphosphate (FDP) significantly activated cardiac RyR channels, increasing open probability (Po) up to approximately 0.6.
• FDP also stimulated [3H]ryanodine binding to cardiac SR membrane vesicles by over 200%.
• The relative effectiveness of sugar phosphates was FDP > G-1-P > F-6-P > G-6-P in activating RyR channels and [3H]ryanodine binding.

Conclusions:

• Sugar phosphate intermediates of glycolysis, particularly FDP, possess novel properties that activate cardiac ryanodine receptors (RyR).
• Changes in glycolytic flux during myocardial ischemia and reperfusion may influence SR Ca2+ release by modulating RyR channel gating.
• This study reveals a new mechanism linking cellular metabolism to cardiac ion channel function.