Tipping Cell Signaling Pathways by Salts
It might surprise you to know that vision, smell, and the plethora of emotions you experience in any given day are all masterfully regulated by a quiet family of cell-signaling molecules in the body called G-Protein Coupled Receptors (GPCRs).
These receptors are complex molecular machines that are switched on by light, small hormones, odorants, and other ligands. In all, there are over 800 different GPCRs in our body and while their functions vary greatly, all possess a very similar design that can be traced back hundreds of millions of years in metazoan evolution.
While all GPCRs have triggers, their response is at the same time regulated by other factors in the cell, namely salts.
“Now that high resolution structures of GPCRs are becoming more readily available, we are beginning to understand where these salt ions bind and how they change the response of receptors in almost every facet of cell signaling,” says Professor Scott Prosser in UTM’s Department of Chemical & Physical Sciences.
In a paper appearing this week in the journal Nature Communications, the Prosser lab and collaborators were able to get one step closer to understanding how salt ions slow down or speed up the action of GPCRs in cell signaling. In this study, a technique their lab employs called Nuclear Magnetic Resonance (NMR) provided a way of identifying states of the receptor that were “on,” “off,” and somewhere in between.
It turns out that there are conserved binding pockets for ions, such as sodium and magnesium, and when engaged, these modify how the machines signal. The detailed NMR observations on both the receptors and on the salts themselves provide new insights into their mechanism of action, but also into new ways of drugging GPCRs. Many labs are now taking aim at these positively charged ion pockets with drugs that displace the salts and take over signaling.
“Forty percent of prescription pharmaceuticals target GPCRs,” says Prosser.
“Salt or cation pockets promise a way for the drug industry to develop new drugs that will take over the cation pocket and modulate the GPCR. The work promises new opportunities for drug discovery.”