PKG Controls cGMP Compartmentation (p 1232)
Location is everything when it comes to cGMP regulation, say Castro et al.
The signaling molecule, cGMP, is produced in heart cells mainly in response to two different vasodilators—atrial natriuretic peptide (ANP) and nitric oxide (NO)—and in two different locations. ANP activates cGMP production at the plasma membrane, whereas NO does it in the cytosol. At both locations, the immediate downstream effector of cGMP activity is the protein kinase PKG. Castro et al have now discovered that in addition to regulating downstream targets, PKG regulates cGMP production itself. And that's not all: PKG worked differently at the two locations. At the membrane, PKG had a positive feedback effect—stimulating activity of the enzyme that produces cGMP—whereas in the cytosol, PKG prompts the breakdown of cGMP by hydrolysis. Thus, under conditions of PKG activation, a steep gradient of cGMP would occur from membrane to cytosol, say the authors. These two different effects of PKG might help to unravel the different mechanisms of action, and the cardiovascular effects, of ANP and NO.
Collagen XV in Heart and Microvessels (p 1241)
Mice that lack collagen XV provide clues to cardiomyopathic processes, report Rasi et al.
Collagen XV is expressed in the extracellular matrix (ECM) of many tissues and is particularly abundant in the heart. Remodeling of the heart's ECM occurs during periods of cardiac stress, after injury, or simply as a result of aging. Understanding this remodeling mechanism could, thus, help researchers understand the cardiomyopathic process. The hearts of mice lacking collagen XV displayed a disorganized ECM and decreased elasticity, as well as unusual myocyte structure, and thinner interventricular septums and ventricle walls. The capillaries in the heart were also affected and displayed irregular luminal shapes, ruptures in the endothelial walls and variations in thickness. Functional analysis revealed that mutant mouse hearts had reduced pumping power, but unexpectedly, this defect improved with age, concurrent with an increase in capillary density and improved myocyte structure. Given that most, if not all, cardiomyopathies are progressive by nature, understanding how the mutant mouse hearts reverse their functional defect could point to an exploitable mechanism for therapy.
Myomasp/LRRC39, a Novel Sarcomeric M-Band Protein (p 1253)
Will et al have identified a novel protein called myomasp, which sits at the M-band of muscle cells and seems to sense how much they stretch.
The M-band is the region of muscle cells' sarcomeric structure that acts as an anchor for myosin-containing thick filaments and provides lateral stabilization to the sarcomere. A few M-band proteins have been identified and characterized, but many more remain unknown. Will et al have now identified myomasp. Found during a bioinformatics search for uncharacterized heart- and muscle-specific genes, myomasp was found to be located to the M-band in rat cardiomyocytes and was shown to interact with myosin. Interestingly, when the team knocked down myomasp, known stretch-sensitive genes, called GDF-15 and BNP, were upregulated. Myomasp knock down also reduced contractile force generation of heart tissue in vitro, impaired heart function, and led to cardiomyopathy in live zebrafish. Certain myopathies are linked with mutations in the region of myosin that interacts with myomasp. Will et al suggest it might be interesting to see whether patients carrying such mutations have altered M-band architecture or myomasp localization. If so, failure to detect overstretching caused by impaired myosin-myomasp interaction could be to blame for these myopathies.
Written by Ruth Williams
- © 2010 American Heart Association, Inc.