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Preferential regulation of rabbit cardiac L-type Ca²⁺ current by glycolytic derived ATP via a direct allosteric pathway

Vito A. Losito, Robert G. Tsushima, Roberto J. Diaz *, Gregory J. Wilson * and Peter H. Backx

1. The activity of Ca²⁺ channels is regulated by a number of mechanisms including direct allosteric modulation by intracellular ATP. Since ATP derived from glycolysis is preferentially used for membrane function, we hypothesized that glycolytic ATP also preferentially regulates cardiac L-type Ca²⁺ channels.

2. To test this hypothesis, peak L-type Ca²⁺ currents (I_Ca) were measured in voltage-clamped rabbit cardiomyocytes during glycolytic inhibition (2-deoxyglucose + pyruvate), oxidative inhibition (cyanide + glucose) or both (full metabolic inhibition; FMI).

3. A 10 min period of FMI resulted in a 40·0 % decrease in peak I_Ca at +10 mV (-5·1 ± 0·6 versus -3·1 ± 0·4 pA pF^-1; n = 5, P < 0·01). Similar decreases in peak I_Ca were observed during glycolytic inhibition using 2-deoxyglucose (-6·2 ± 0·2 versus -3·7 ± 0·2 pA pF^-1; n = 5, P < 0·01) or iodoacetamide (-6·7 ± 0·3 versus -3·7 ± 0·2 pA pF^-1; n = 7, P < 0·01), but not following oxidative inhibition (-6·2 ± 0·4 versus -6·4 ± 0·3 pA pF^-1; n = 5, n.s.). The reduction in I_Ca following glycolytic inhibition was not mediated by phosphate sequestration by 2-deoxyglucose or changes in intracellular pH.

4. Reductions in I_Ca were still observed when inorganic phosphate and creatine were included in the pipette, confirming a critical role for glycolysis in I_Ca regulation.

5. With 5 mM MgATP in the pipette during FMI, peak I_Ca decreased by only 18·4 % (-6·8 ± 0·6 versus -5·5 ± 0·3 pA pF^-1; n = 4, P < 0·05), while inclusion of 5 mM MgAMP-PCP (,-methyleneadenosine 5'-triphosphate, Mg²⁺ salt) completely prevented the decrease in peak I_Ca (-6·9 ± 0·3 versus -6·5 ± 0·3 pA pF^-1; n = 5, n.s.).

6. Together, these results suggest that I_Ca is regulated by intracellular ATP derived from glycolysis and does not require hydrolysis of ATP. This regulation is expected to be energy conserving during periods of metabolic stress and myocardial ischaemia.

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