A closer look at cardiac muscle cells
Heart failure is defined as the inability of the heart to supply adequate blood flow to meet the body’s needs. Heart muscle cells of patients with heart failure have abnormal regulation of calcium, and the Calcium Cycling and Novel Therapeutic Approaches for Heart Failure network studies the upstream and downstream molecular pathways related to such abnormalities.
One such pathway involves the hormone adrenaline. The body increases the release of adrenaline in an attempt to stimulate the failing heart. Over the short term this stimulation helps the heart compensate, but over the long term the stimulation becomes harmful and actually worsens heart failure.
There are two types of receptors for adrenaline located on the surface of heart muscle cells, β1AR andβ2AR. Both types of receptors respond to adrenaline activation by generating the same molecular signal (cyclic AMP), but the two types of receptors have different effects on the cell.
To understand how the two receptors are able to cause such distinct responses in the heart, a group of researchers, including network members Martin J. Lohse and Sian E. Harding, used a new technique called scanning ion conductance microscopy (SICM). SICM allows the analysis of specific regions of the cell surface with unprecedented detail. Using SICM and chemical probes that emit fluorescent signals when the βARs are stimulated, the investigators demonstrated that β1ARs are widely distributed throughout the membrane of healthy heart muscle cells. In contrast, β2ARs are exclusively found at the T tubules. T-tubules are specific regions of the cell membrane that contain many ion channels. The channels allow the voltage of the muscle cell to change very quickly, as occurs when the cell receives a signal to contract. In cells from animals with heart failure, β2ARs were redistributed across the cell membranes, like the β1ARs.
This work, which was reported in the March 26, 2010 issue of Science, advances our understanding of the molecular changes that occur with heart failure. The findings may lead to improved design of beta-blockers, a class of drugs that is already a mainstay of heart failure and arrhythmia treatment.
This research was also funded by the Wellcome Trust, Action Medical Research, the UK Biotechnology and Biological Sciences Research Council, and the UK Medical Research Council.
Click on the title to access the article in Science: β2-Adrenergic receptor redistribution in heart failure changes cAMP compartmentation.