Our prior work has shown that Na+current (INa) affects sarcoplasmic reticular (SR) Ca2+release by activating early reverse of the Na+-Ca2+exchanger (NCX). The resulting Ca2+ entry primes the dyadic cleft, which appears to increase Ca2+channel coupling fidelity. It has been shown that the skeletalisoform of the voltage-gated Na+channel (Nav1.4) is the main tetrodotoxin(TTX)-sensitive Navisoform expressed in adult rabbit ventricular cardiomyocytes.Here I tested the hypothesis that it is also the principal isoform involved in the priming mechanism. Action potentials (AP) were evoked in isolated rabbit ventricular cells loaded with fluo-4, and simultaneouslyrecorded Ca2+transients before and after the application of either relatively low doses of TTX (100nM),the specific Nav1.4 inhibitor μ-Conotoxin GIIIB or the specific Nav1.1 inhibitor ICA 121430. While AP changes after the application of each drug reflected the relative abundance of each isoform, the effects of TTX and GIIIB on SR Ca2+ release (measured as the transient maximum upstroke velocity) were no different. Furthermore, this reduction in SR Ca2+ release wascomparable to the value that we obtained previously when total INawas inactivated with a ramp applied under voltage clamp. Finally, SR Ca2+ release was unaltered by the same ramp in the presence of TTX or GIIB. In contrast, application of ICA had no effect of SR Ca2+release. Theseresults suggest that Nav1.4 is the main Nav isoform involved in regulating the efficiency ofexcitation-contraction coupling in rabbit cardiomyocytes by priming the junction via activation of reverse-mode NCX.
Activation of Reverse Na/Ca Exchanger by Skeletal Na Channel Isoform Increases Excitation-Contraction Coupling Efficiency in Rabbit Cardiomyocytes
