Whenever we look at something bright, say your computer screen or the stars in the night sky, the “ion channel” in our eyes gets closed due to light stimulation, marking the ultimate stage of a series of biochemical reactions.
When this happens the flow of calcium ions eventually stops.
The biochemical signal is converted into an electrical signal that navigates through the nervous system and further gets processed by the brain.
Our eye has two kinds of photoreceptor cells (i.e, the light detecting): rod cells and cone cells.
Rod cells are more abundant and sensitive to low levels of light and do the process mentioned above.
A team of Swiss Scientists led by Jacopo Marino has improved our understanding of the structural mechanisms that go behind the working of rod cells with the help of calmodulin[1].
Calmodulin
Calmodulin is a calcium-binding protein that plays a crucial role in regulating various cellular processes in eukaryotic cells. It is involved in the activation of enzymes, ion channels, and other proteins by binding to them in a calcium-dependent manner.
Significance of Calmodulin in Eyes
Calmodulin plays a critical role in regulating various physiological processes in the eyes.
In the retina, calmodulin is involved in the regulation of photoreceptor cell function, including the activation and deactivation of rod and cone CNG channels, which are important for the detection and processing of light signals.
Rod CNG channel
The rod cyclic nucleotide-gated (CNG) channel is a type of ion channel that is found in the outer segment of rod cells, which are specialized photoreceptor cells in the retina of the eye.
This channel plays a crucial role in the detection of light by rod cells, which is essential for our ability to see in low-light conditions.
Calmodulin also modulates the activity of ion channels and pumps in the retinal pigment epithelium, which is responsible for maintaining the health and function of the photoreceptor cells.
The protein is involved in the regulation of calcium signaling pathways in the eyes, which are important for various cellular processes such as neurotransmitter release and gene expression.
Dysfunction or dysregulation of calmodulin in the eyes can lead to various vision disorders, including retinal degeneration and abnormal responses to light stimuli.
Interaction of Calmodulin and Rod CNG channel
The rod CNG channel is made up of four subunits that create a tetrameric structure, each with six transmembrane domains.
The binding of cyclic guanosine monophosphate (cGMP) to a receptor site in the channel’s N-terminus activates it.
This interaction causes a conformational shift in the channel, which opens the pore and allows positively charged ions like sodium and calcium into the cell.
But nonetheless, one quirk of the channel is that three subunits, known as subunit A, are identical, but a fourth, subunit B, is distinct.
It was known for a long time that subunit B binds the calmodulin and this feature is present in all animals, still, the true nature of its role remains undetected.
Researchers can now provide a three-dimensional image of what is truly going on.
Using cryo-electron microscopy and mass spectrometry, they discovered that as calmodulin binds, the ion channel becomes more compressed.
Researchers quote that this is nature’s way of keeping the channels closed.
The purpose of keeping the channels closed is to reduce the spontaneous opening of channels which would reduce background noise, allowing our eyes to be sensitive to dim light.
Mass Spectrophotometry Helps Researchers Solve the Mystery
Researchers report that it was difficult to obtain the structure of calmodulin and the ion channel binding.
Calmodulin and Rod CNG interact at a very fluid region of the channel where it is prone to spin freely.
This makes obtaining high-resolution structural information via cryo-electron microscopy extremely difficult.
CaM joins the CNGA and CNGB subunits, causing structural alterations in the channel’s cytosolic and transmembrane regions.
The conformational changes generated by CaM in vitro and in the native membrane were mapped using cross-linking and restricted proteolysis-coupled mass spectrometry.
They postulated that CaM is a rod channel constitutive subunit that ensures high sensitivity in low light.
The mass spectrometry-based approach used by the researchers is generally applicable for evaluating the effect of CaM on ion channels in tissues of medical interest where only minute quantities are accessible.
References
- Jacopo Marino et al., ‘Structural basis of calmodulin modulation of the rod cyclic nucleotide-gated channel | PNAS’, PNAS, 3 April 2023, https://www.pnas.org/doi/10.1073/pnas.2300309120[↩]
