New view of heart muscle cells shows movement of ß2 adrenergic receptors
Lynn Savage, lynn.savage@photonics.com
Building better beta-blockers for various heart ailments
may be on the horizon because of a novel imaging technique used by researchers at
Imperial College London.
Beta-blockers are drugs that inhibit the action of β
1 and β
2 adrenergic
receptors – G-protein-coupled receptors that reside on the surface of cardiac
muscle cells, or cardiomyocytes. Both β
1 and β
2 mediate specific events that affect
heart function; for example, β
1 strongly stimulates heart contractions, while β
2
has a mildly stimulating effect but a strong cardioprotective one. Although the
roles played by β
1 and β
2 adrenergic receptors are well-known, their location inside
the cardiomyocytes and the potential effects their placement might have on their
functionality have remained undetermined.
Dr. Julia Gorelik and her colleagues at the college and at the
University of Würzburg in Germany used a nonoptical imaging technique called
scanning ion-conductance microscopy (SICM) to examine where in the heart cells β
1
and β
2 were sited and how they behaved when activated. They eschewed more typical imaging
techniques, such as electron microscopy, because of insufficient expression levels
of G-protein-coupled receptors in general.
SICM works by using an electrolyte-filled glass pipette with a
50- to 100-nm tip as a scanning probe that traverses the entire cell. Unlike the
cantilever tip of an atomic force microscope, the nanopipette does not contact the
cell or its components. Instead, it measures changes in ion flow through the pipette.
The resolution of the device is equal to the diameter of the pipette’s tip,
which means that the structural features of the cardiomyocyte, including its crests
and transverse tubules (T-tubules), are readily visualizable.
To see the effect that β
1 and β
2 have on heart muscle, the researchers
used SICM to locate the receptors and used Förster resonance energy transfer
(FRET) to look for production of cyclic adenosine monophosphate (cAMP), a molecule
important to cell signaling. For the FRET measurements, they used a Nikon microscope,
an Osram mercury lamp and a Hamamatsu CCD camera.
They locally stimulated β
1 and β
2 at the T-tubules and crests
of rat cardiomyocytes. They found that the β
1 receptors dramatically decreased FRET
signals in both locations, which showed activation of cAMP production. The β
2-cAMP
FRET response occurred only at the T-tubules, not at the cell crests. From this,
the researchers concluded that the β
2 receptors are normally located at the T-tubules
but change location to match β
1 receptors when the heart muscle is damaged. They
believe that this shift in distribution could affect the ability of β
2 to protect
cardiac muscle during heart failure.
The new information regarding translocation of β
2 adrenergic receptor
could provide the next step toward improving beta-blocker drugs currently used to
thwart the cascade of damage during heart failure and could provide insight about
whether β
1 or β
2 should be blocked together or separately.
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