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 Ca2+ 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.
Hilgemann
Donald W
DW
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9040, USA. donald.hilgemann@utsouthwestern.edu
D000818:Animals; D015640:Ion Channel Gating / Q000502:physiology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000502:physiology*
D019831:Sodium-Calcium Exchanger