Sensing the environment is an essential aspect for humans, as it facilitates the next potential event to take on. It allows us to elicit and react to many types of environmental cues that might trigger fight or flight responses as well as generate responses to relax. Just as the pain sensors in our fingers as well go to touch a hot stove provoke us to react me quickly removing our hand. Cells are exactly the same, just at the micro- to nano- meter scale. One of the main sensors on cells are proteins known as receptors.
Receptors are found throughout the entirety of the cell, especially at the surface. Some receptors sense growth hormones, mechanical stress, pathogen sensing, and respond accordingly. These various types of recognition events will elicit a response that will “activate” the receptor to induce various processes that will allow the cell to respond appropriately in such a way that it will benefit, just as removing our hand for a burning stove was the beneficial choice to protect ourselves.
For many years it has been demonstrated that receptors exist as monomers. But upon ligand stimulation, they are dimerized before they elicit a response. Through a recent science article, this “dimerization” model may be problematic for some skeptic scientists.
Dr. Maruyama from the Okinawa Institute of Science and Technology in Japan, shows in his article, Activation of transmembrane cell-surface receptors via a common mechanism? The “Rotation model” that this dimerization phenomenon may not be all that correct. The dimerization-based model demonstrates that without ligand stimulation, the monomeric form of the receptor is free and existing throughout the cell. When the ligand is present, it causes receptor dimerization, thus leading to activation of the receptor. The dimerization model, according to Dr. Maruyama, may be dangerous towards the cell’s well being. The plasma membrane, where many receptors are located, is not a static, but rather a dynamic entity experiencing constant change. These constantly moving receptors will come into contact with other molecules, such as proteins, lipids, and other receptors including other monomeric forms of itself. By this mechanism, there is a high chance for random receptor activation due to accidental dimerization which inevitably lead to an improper cellular response to its external environment which is usually the case with several diseases including cancer.
Dr. Maruyama describes the potential new receptor activation model, known as the “rotation model,” that may convey a different perspective from the dimerization model. He analyzed many different types of receptors showing their structural similarities and mechanisms for activation among each other. Dr. Maruyama demonstrated that during particular signaling events of receptors, the dimerized receptor, rotates and angles itself in a particular orientation. This brings in the model, hypothesizing that receptors are always stably dimerized when present at the cell surface. The characteristics of these receptors contain a flexible domain outside the cell connected by a rotatable transmembrane domain connected to a rigid cytosolic domain within the cell. Once an appropriate ligand is present and binds to this stable dimer complex, the flexible domain outside the cell becomes rigid “rotates the transmembrane domain” and the domain within the cell becomes flexible. The flexible cytosolic domain is now able to interact with other molecules within the cell and continue cellular signaling to mediate important processes (Figure 1).
Figure 1. The characteristics of Dr. Maruyama’s receptor activation “rotation” model.
This is a very innovative activation concept and Dr. Maruyama’s hypothesis has all the right information to back this model. Like every great idea and discovery, further testing and information is required in order to validate the model. This model upon validation will pave the way for the development of novel drug targets in diseases including cancer. The unique rotating transmembrane domain model demonstrates a new regulation pattern that may provide new insight into how receptors sense and potentially allow for the design of new drug therapeutics for pharmaceuticals for diseases.
Maruyama, I. N. (2015). Activation of transmembrane cell-surface receptors via a common mechanism? The “rotation model.” BioEssays, 37(9), 959–967. http://doi.org/10.1002/bies.201500041