ARCHIVED - Secrets of the Heart Revealed

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October 05, 2005— Ottawa, Ontario

Cover of nature Chemical Biology Showing the fluorescent receptors on the surface of the heart cell

Using customized optical microscopy, NRC scientists have a front row seat to watch heart cells in action. Their article, published in September's Nature Chemical Biology, shows how receptors on heart muscle cells respond to hormonal signals from their environment.

Receptors are the gateways to the cell that regulate chemical traffic and serve as the cell's 'eyes and ears'. This particular discovery allows scientists to watch as Beta-adrenergic receptors (β2AR) in the heart initiate the flight or fight response. Hormones in the bloodstream interact with the receptors which, in turn, tell the heart's muscle cells that trouble is on the way so they had better get pumping.

"Fundamentally, these receptors are the communicators between the blood stream and the muscle cells that control the heart rate," explained Dr. John Pezaki, study co-author and Associate Research Officer at the NRC Steacie Institute for Molecular Sciences (SIMS).

The NRC team was able to visualize this biological phenomenon using Near-Field Scanning Optical Microscopy (NSOM). This imaging technology channels light to the cell through a sub-micron sized fibreoptic probe. The probe's tiny aperture, as small as 50 nanometers in diameter, prevents the diffraction of light that limits the resolution of conventional microscopy .

Fluorescently-labelled Beta Andronergic Receptors seen with conventioal microscopy in a. and NSOM in b. Resolution of conventional microscopy is limited due to the diffraction of light as compared to the resolution with NSOM.
Fluorescently-labelled Beta Andronergic Receptors seen with conventioal microscopy in a. and NSOM in b. Resolution of conventional microscopy is limited due to the diffraction of light as compared to the resolution with NSOM.

"Most other kinds of optical microscopy have a much larger depth of field where you can see through the cell. However, if you want to get a very high-resolution picture of the surface, conventional microscopy is not ideal," said Dr. Linda Johnston, the imaging expert for the study and Program Leader at NRC-SIMS.

Few groups in the world have the multi-disciplinary expertise to do this type of work due to the technical difficulty of building the probe and working with delicate biological structures.

"We've had everyone from physics to biology and chemistry involved in aspects of this project," said Johnston.

Labeling the receptors with fluorescent tags allows the researchers to observe them in action. Their pictures show the β2AR clustering together in pits called caveolae. This organization may be necessary for the receptors to work properly.

"Caveolae are invaginations that are thought to be important for scaffolding," said Pezacki. "Indirect evidence suggests that they are an anchor for the signal transduction machinery so they can accept the signal efficiently."

These results challenge science's basic theories of how cell membranes work. The 'fluid mosaic' model assumes that cell membranes are semi-fluid pools where molecules float around and meet up with other molecules more or less randomly. The deliberate receptor clustering seen in this study suggests that the cell membrane is a lot more organized that we had previously thought.

The β2A receptors visualized in this study are part of the larger G-coupled protein receptor family that regulates cellular activities throughout the body. This study adds an extra dimension to our understanding of how our cells sense and respond to their external environment, a question of great interest to science and medicine.

"Membrane protein receptors are the target for 30 to 50% of the pharmaceutical drugs that are currently on the market," said Pezacki. "They are targets of a large number of drugs such as anti-asthmatics and anti-depressants."

Dr. Pezacki summarizes the scientific and clinical importance of understanding how receptors work. "Receptors are the fundamental way that the cell takes an extracellular signal and processes it. They're the point through which cells understand their surroundings. This method is one way we can get closer to how receptors work in their native environment."

This perfected biological imaging technique could eventually lead to the development of novel therapeutics for regulating heart arrhythmias.

Enquiries: Media relations
National Research Council of Canada

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