New insights into the molecular and cellular workings of the cardiac Na⁺/Ca²⁺ exchanger

The cardiac Na⁺/Ca²⁺ exchanger (NCX1) is almost certainly the major Ca²⁺ extrusion mechanism in cardiac myocytes, although the driving force for Ca²⁺ extrusion is quite small. To explain multiple recent results, it is useful to think of the exchanger as a slow Ca²⁺ buffer that can reverse its function multiple times during the excitation-contraction cycle (ECC). An article by the group of John Reeves brings new insights to this function by analyzing the role of regulatory domains of NCX1 that mediate its activation by a rise of cytoplasmic Ca²⁺. It was demonstrated that the gating reactions are operative just in the physiological range of Ca²⁺ changes, a few fold above resting Ca ²⁺ level, and that they prevent the exchanger from damping out the influence of mechanisms that transiently increase Ca²⁺ levels. Furthermore, exchangers with deleted regulatory domains are shown to reduce resting Ca²⁺ to lower levels than achieved by wild-type exchangers. A study by the group of Kenneth Philipson demonstrated that the NCX1 regulatory domain can bind and respond to Ca²⁺ changes on the time scale of the ECC in rat myocytes. At the same time, studies of transgenic mice and NCX1 knockout mice generated by the Philipson group revealed that large changes of NCX1 activity have rather modest effects on ECC. Simple simulations predict these results very well: murine cardiac ECC is very sensitive to small changes of the Na⁺ gradient, very sensitive to changes of the sarcoplasmic reticulum Ca²⁺ pump activity, and very insensitive to changes of NCX1 activity. It is speculated that the NCX1 gating reactions not only regulate coupled 3Na⁺:1Ca²⁺ exchange but also control the exchanger's Na⁺ leak function that generates background Na ⁺ influx and depolarizing current in cardiac myocytes.