Transmural gradients of repolarization and excitation-contraction coupling in mouse ventricle.

The effects of changes in action potential waveform on excitation–contraction coupling in mammalian ventricle were first identified almost 40 years ago.1 Many important details concerning the relationship between action potential duration and tension development have been elucidated.2 Recent work has demonstrated significant effects on the intracellular Ca transient and excitation–contraction coupling of early repolarization of the action potential, which is strongly regulated by a Ca -independent transient outward K current denoted Ito. The molecular physiology and some aspects of the pharmacology of this current are now quite well understood, based, in part, on a series of comprehensive articles from the Nerbonne et al,7,8 Strauss and Campbell,9 and others.6 Interestingly, a somewhat similar transient outward K current is expressed in neurons10 and in selected regions near the intraventricular septum of mammalian hearts.11–13 One of the most striking features of the transient outward K current in mammalian ventricle is the difference in its transmural expression, with significantly higher expression levels in epithan in endocardium14 (see also references 8, 9, 11). The basis for this transmural heterogeneity, and also for the higher levels of expression in the right ventricle compared with the left, continues to be a topic of intense investigation. Significant new information and plausible working hypotheses for the way in which this heterogeneity can regulate excitation–contraction coupling are a focus of work from the laboratory of Santana et al.15 Their most recent article is published in this issue of Circulation Research.16 This article provides new evidence for the ways in which the calcineurin/NFATc3 signalling complex can contribute to the transmural gradient of Ito in the left ventricle of the adult mouse heart. The magnitude of Ito, Kv4.2, and Kv4.3 have been reported to be reduced by both acute and long-term activation of various receptor-mediated pathways in response to neurohormonal factors. Moreover, gene transfer technology has provided new insights concerning the role of Ito, Kv4.2, and Kv4.3 in the hypertrophic response.6,17,18 A number of lines of evidence suggest that the reduction of Ito (and of Kv4.2 and Kv4.3) can prolong APD, increase Ca entry via ICaL, and activate calcineurin phosphatase activity. Calcineurin in turn dephosphorylates NFAT which is in the cytosol. Once dephosphorylated, NFAT can translocate into the nucleus and (with several other factors) can activate transcription and protein synthesis.6,16,17 Accordingly, these studies have suggested that prolongation of APD can result in protein synthesis and contribute to a hypertrophic response or other forms of adaptation. In contrast, the present article by Rossow et al16 concludes that the activation of the calcineurin pathway occurs before changes in Kv4.2/Ito in mouse ventricle and that this is a significant causative factor in the transmural heterogeneity of APD. Alternate biochemical pathways which contribute to this heterogeneity have been identified previously. These include contributions from a homeodomain transcription factor Irx5,19 the KChIPs beta subunit for Kv4.2, 4.3,8,9,20–22 and association with the CD26-related dipeptidyl aminopeptidase-like protein, DPPX.23–25 Attempts to place the elegant work by the Santana laboratory16 into the context of the pathophysiological mechanisms for excitation-contraction coupling in the left ventricle will require some additional work and integration of a number of important considerations. These include: