Hopkins scientists find new calmodulin mechanism

Imagine falling down and getting a wound that won’t heal, or eating and not being able to digest your food, or even not being able to remember events that have just occurred. These processes are only a few of the many that we take for granted but are so vital that without them, our standard of living would be severely compromised. And each of them is partly contingent upon a single 148 amino acid-long protein, calmodulin, which modulates the chains of signals within our cells to allow us to digest, remember and heal.

Dr. David Yue, a professor in the Biomedical Engineering and Neuroscience departments of the Johns Hopkins University School of Medicine, has created a revised model of how calmodulin works.

Calmodulin is one of the most important proteins utilized in signal transduction pathways, the means by which a cell reacts and responds to changes in the environment. Researchers think that the calcium-binding protein regulates the opening and closing of ion channels that either allow or block ions from entering or leaving a cell. Ion channels are crucial components of various cell signaling pathways and cellular processes such as smooth muscle contraction, movement within a single cell and the bodily immune response.

Previously, however, researchers thought that only the activated form of calmodulin had any role in regulating the opening and closing of ion channels, while the dormant form of calmodulin awaited calcium ions to bind to it before being able to affect channels.

Yue discovered that calmodulin without calcium bound to it — that is, apocalmodulin (apoCaM) — does in fact bind to and boost the opening of ion channels, rather than being dormant. In fact, apoCaM markedly upregulates the opening of these ion channels, and upon the binding of calcium to apoCaM to make calmodulin, the inhibition simply reverses the initial upregulation achieved by the apoCaM.

Yue’s revised view of calmodulin is powerful in its implications for diseases involved in ion channel control because it allows researchers to target the correct function of calmodulin and apoCaM. Yue’s research, published in the journal Cell, was achieved by using tests such as low-noise electrophysiology to observe single channels and measuring the voltage and current across the channel in varying concentrations of both calmodulin and apoCaM.

Because of calmodulin’s wide range of activity, the research affects the understanding of many biological mechanisms. One consequence of the revised view of apoCaM is the knowledge that elevated levels of it might predispose a person to calcium ion-related neurodegeneration associated with Parkinson’s disease. Yue’s view also allows researchers to differentiate between calmodulin and apoCaM dysfunction and to generalize that certain disease mutations could also alter apoCaM binding.

Signal transduction pathways in the body are incredibly complex, and this reveals a use for a seemingly “dormant” form of a protein. The research has led to a radically different view of how cells control the materials that come in and out of it and will allow scientists to create more refined models of the roles of ion channels in the multifarious diseases related to channel control and regulation.