How often are we aware of what’s going on in individual cells in our bodies? We are made
of trillions of cells, yet notice very few. For example, neutrophils, a type of white blood cell
circulate throughout our bodies protecting us from infection.
Every hour of our life, billions of these cells are born and die.
Yet we don’t notice. In contrast, we are exquisitely
aware of some cells such as nerve cells in our eyes and other sensory organs.
At the back of the eye is the retina, containing light sensing cells called photoreceptors.
As discussed in a previous video, our dark-adapted rods can detect individual photons that activate
a light-sensing molecule within them. This means that our visual system has astonishing
sensitivity: we can detect events affecting not just a single cell, but individual molecules.
How we go from activating a single molecule, to affecting the whole rod so that it can inform
the brain is through a process of immense and rapid amplification called phototransduction.
Phototransduction is the process by which light is converted into
electrical signals in photoreceptors. There are 2 types of photoreceptors.
In this video, we’ll be focusing on the rods. A similar process occurs in cones,
but they are less sensitive to individual photons, requiring much brighter light.
The light-sensitive region of the rod is here, where inside there are numerous disc-shaped
structures stacked atop each other. These discs are membranes that contain millions
of light-sensing molecules called rhodopsin. What happens when light activates rhodopsin?
Rhodopsin has two parts: a small molecule called retinal attached to a protein called opsin. When
light is absorbed, it results in a rearrangement of a double bond in the middle to change it from
this to this. This tiny rearrangement of retinal pushes on parts of the rhodopsin,
activating it. The challenge is this:
This activated rhodopsin must produce a signal large enough to affect the whole cell.
In addition to rhodopsin, there are 2 other important proteins in the disc membranes:
transducin and phosphodiesterase. After a photon activates a rhodopsin,
the rhodopsin will activate transducin proteins it encounters.
The activated transducin in turn will bind to and activate phosphodiesterase.
Effectively, transducin is an intermediary between rhodopsin and phosphodiesterase.
Having this chain of activation allows for amplification. Here’s how:
Recall from chemistry that molecules in solution are in constant motion.
Rhodopsin, water molecules, and all other molecules in the disc membrane
are constantly colliding with each other. These collisions bring rhodopsin into contact
with many transducins, activating them. Each activated transducin, in turn, will bind to
and activate phosphodiesterase. In these visualizations, time is slowed down and
the violent motions of the molecules are reduced and simplified so we can see what’s happening.
This is the first step of the amplification: one activated rhodopsin leads to many activated
phosphodiesterase proteins in a few hundred milliseconds.
In the dark, rods contain many small molecules called cyclic GMP.
Cyclic GMP is also in constant random motion, and when it encounters activated phosphodiesterase,
it is converted into another chemical. For visual simplicity,
I’m showing the cyclic GMP disappearing when they encounter activated phosphodiesterase,
as cyclic GMP is the important molecule for phototransduction.
This is the second step of amplification: each phosphodiesterase will destroy several cyclic
GMP molecules. Thus, a single activated rhodopsin will result in the loss of thousands of cyclic
GMP molecules, resulting in a decrease in the concentration of cyclic GMP.
Rods have a constant circulating electric current in the dark. At one end of the cell,
positive charge, in the form of ions like sodium are constantly pumped out of the cell.
By pumping these positive charges out of the cell, the cell becomes negatively charged,
which we’ll show in blue like this. The cell membrane is an electric
insulator because ions cannot freely cross it to reenter the cell. But there are proteins called
ion channels that are like tunnels allowing charge to enter the cell at the other end.
When these ion channels are open, sodium ions can move through these to reenter the cell.
Why do they enter the cell? Recall that opposite charges attract: The cell is slightly negatively
charged, attracting the positive ions. How does this relate to cyclic GMP? Cyclic
GMP can bind to these channels. The channels are open when cyclic GMP is bound, and charge
can enter the cell. The channels are closed when cyclic GMP is not bound to the channel, blocking
the entry of positive charge into the cell. When cyclic GMP is plentiful, it will bind to
and unbind from the channel many times per second, because it is only weakly attached to the channel.
After a photon activates rhodopsin, thousands of cGMP molecules are destroyed by phosphodiesterase,
depleting the cyclic GMP in that part of the cell. This causes the nearby channels to close,
reducing the amount of positive charge entering. The pumps at the other end of the rod keep pushing
positive charge out of the cell. As a result, the cell becomes more negatively charged.
This is the last step of phototransduction: the loss of thousands of cyclic GMP molecules
leads to closing of a small fraction of the channels. This makes the electric potential
across the cell membrane more negative by about a millivolt. This electric signal,
though small, is enough to affect the cell and be passed on to other nerve cells.
And all of this occurs in less than a second. Any one of the millions of rhodopsin molecules
in the rod can activate this cascade. Brighter lights made of more photons
can activate multiple rhodopsins at the same time. More activated rhodopsins will lead to
more destruction of cyclic GMP and a greater electric signal from closing more channels.
After about a second, the rhodopsin becomes inactivated, along with transducin
and phosphodiesterase. Other proteins return cyclic GMP levels to normal,
and the channels reopen, returning the rod to a more positive membrane potential.
The amplification in the phototransduction cascade is immense. Realize that the whole process begins
with a tiny change to a single molecule. No atoms are added or removed and even the number
of bonds in the molecule remains the same. Phototransduction relies on random molecular
encounters between molecules. Sometimes the rhodopsin will activate more transducins and
sometimes fewer. But because rhodopsin activates many molecules, one photon can be distinguished
from two. Phototransduction is one example of a more general phenomenon: all of life’s
chemical reactions rely on similar random collisions to what you see here. Quantitative
thinking is essential for understanding the chemical reactions fundamental to biology.
I made these animations to let you see that biological processes
are physical processes to which we can apply our physical and mathematical intuition. Also,
I invite you to be curious: Notice that rhodopsin and phosphodiesterase are confined to a plane,
diffusing in 2 dimensions instead of 3. How does this affect the collision rates? Another question.
Increasing temperature will increase the speed of molecules. How might phototransduction be
different in cold blooded animals compared to us? What other questions do you have? Put your
thoughts or questions in the comments section. If there’s interest, I can make a video discussing
these, as there’s some surprising biophysics and math there. If you’re interested in more,
see my previous video exploring whether the signal to noise in rods lets us see individual photons.