NFAT-Dependent Excitation–Transcription Coupling in Heart

Abstract

See related article, pages 733–742 Two articles from the laboratory of Stanley Nattel,1,2 one article in this issue of Circulation Research and an article in an upcoming issue of the journal, address an important, long-standing question in cardiac physiology: what are the molecular mechanisms underlying rate-dependent changes in the function of voltage-gated K+ and L-type Ca2+ channels in ventricular and atrial myocytes? Through a series of elegant experiments, they provide an interesting and unexpected answer to this difficult conundrum. In many ways, these 2 studies are excellent examples of how implementation of the problem-solving approach of Prof George Polya3 remains an invaluable tool to resolve complex problems in biology. Accordingly, I use a “Polyaesque” framework below to illustrate the importance and broad implications of the work by Xiao et al1 and Qi et al.2 Multiples studies indicate that chronic increases in heart rate are associated with changes in the waveform of the action potential (AP) of atrial and ventricular myocytes. In atria, sustained, high-frequency electric activation rates are associated with shortening of the AP of atrial myocytes.4,5 This results in a decrease in the refractory period of the AP of atrial myocytes, which could increase the probability of atrial fibrillation, the most common cardiac arrhythmia. Interestingly, a decrease in depolarizing L-type Ca2+ channel current ( I Ca) function has been linked to decreased atrial AP duration during tachycardia.6,7 Downregulation of the transcript and protein levels of the pore-forming α subunit of L-type Ca2+ channels (Cav1.2) underlie decreased I Ca function during atrial tachycardia and fibrillation. Like atrial myocytes, long-term tachycardia could also alter the waveform of the AP …