Two independent studies have determined how changes in the density of different ion channels in the surface membrane of heart muscle cells can lead to life-threatening abnormal heartbeats, according to research to be published in the August 24 issue of the Journal of Clinical Investigation.
As Gail Robertson, at the University of Wisconsin — Madison, discusses in an accompanying commentary, these important studies provide new insight into the complex array of mechanisms controlling our heartbeat and how they can be perturbed.
The coordinated contraction of heart muscle cells that ensures a normal heartbeat is controlled by an electrical current that passes from one heart muscle cell to the next and along a special conduction system within the heart. A block in conduction of this electrical current disrupts the heartbeat and is the most common cause of pacemaker implantation. Many diseases that cause conduction block, including progressive familial heart block type I (PFHBI), are inherited. Olaf Pangs and colleagues, at Universitδt Hamburg, Germany, have now linked a mutation in the gene TRPM4 with PFHBI in 3 branches of a large South African Afrikaner pedigree with the disease. The TRPM4 gene is responsible for generating an ion channel that the authors found to be expressed at highest levels in a crucial region of the special conduction system within the human heart. Importantly, the PFHBI-associated mutation increased levels of the TRPM4 channel at the cell surface and blunted conduction of the electrical current.
A noninherited cause of an abnormal heartbeat is low levels of potassium (K+) in the blood, which can trigger life-threatening changes to the heartbeat. Shetuan Zhang and colleagues, at Queen's University, Ontario, have now determined in rabbits that low levels of potassium in the blood cause decreased levels of the IKr ion channel at the surface of rabbit heart muscle cells. Specifically, low levels of potassium caused increased internalization and degradation of the channels. Similarly, low levels of potassium in culture medium decreased levels of the human counterpart, HERG, in cell lines. These data provide insight into how a drop in levels of potassium in the blood can cause sudden cardiac death.
- Kruse et al. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. Journal of Clinical Investigation, 2009; DOI: 10.1172/JCI38292
- Guo et al. Extracellular K concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines. Journal of Clinical Investigation, 2009; DOI: 10.1172/JCI39027
- Gail A. Robertson. Endocytic control of ion channel density as a target for cardiovascular disease. Journal of Clinical Investigation, 2009; DOI: 10.1172/JCI40427
Cite This Page: