Molecular Medicine Israel

Following a pathway leading to heart problems

Proceedings of the National Academy of the Sciences USA 108, 18500–18505 (2011); Doi: 10.1073/pnas.1103300108
Klaiber, M., Dankworth, B.,Kruse, M., Hartmann, M., Nikolaev, V.O., Yang, R.-B., Volker K., Gaβner, B., Oberwinkler, H., Feil, R., Freichel, M., Groschner, K., Skryabin, B.V., Frantz, S., Birnbaumer, L., Pongs, O. & Kuhn, M.
“A cardiac pathway of cyclic
GMP-independent signaling of guanylyl cyclase A, the receptor for atrial natriuretic peptide”.

A recently discovered signaling pathway in heart cells explains how calcium levels can increase and cause unnecessary cell death.

High levels of calcium ions in heart muscle cells can trigger the thickening of the heart wall and arrhythmia, but physiologists know little about exactly how calcium accumulates. Now, Michaela Kuhn at Würzburg University, Germany, with colleagues from several institutions including Ruey-Bing Yang at Academia Sinica, Taiwan, have discovered a signaling pathway that controls the levels of calcium ions in heart muscle cells.

Atrial natriuretic peptide (ANP) is an important hormone secreted by heart muscle cells, which helps to lower blood pressure and control the chemical balance in cells. ANP generally functions by binding to a receptor molecule called GC-A, and is involved in a well-known signaling pathway governed by the messenger molecule cGMP that prevents calcium ions from reaching toxic levels. However during heart muscle thickening — cardiac hypertrophy — ANP levels increase dramatically and its functioning suffers because the GC-A receptors become desensitized to it.

Kuhn and colleagues identified the previously unknown signaling pathway in mice with cardiac hypertrophy. The desensitized GC-A receptors stimulate the pathway independently of cGMP, activating ion channels to allow elevated levels of calcium ions to enter and ultimately kill the cell.

This finding provides a unique example of how signaling processes change during pathological conditions, and could aid the development of new treatments for heart problems.


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