09:52am Thursday 16 August 2018

A step forward in understanding key enzymes involved in hypertension

Research carried out at Cardiff University has provided insight into the regulation of two proteins that are implicated in hypertension.

In the mid-2000s, it was found that two proteins called SPAK and OSR1 play important roles in regulating sodium, potassium and chloride levels in animals and humans. Due to this and the fact that SPAK and OSR1 are regulated by other proteins that are mutated in hypertension, understanding the function of SPAK and OSR1 became instrumental in understanding hypertension and finding new and more effective ways of treating it. Now, Dr. Youcef Mehellou from Cardiff School of Pharmacy and Pharmaceutical Sciences has published two studies that provide key insights into the regulation of SPAK and OSR1 kinases.

The first study reported on how SPAK and OSR1 bind another protein known as MO25. The binding of this latter protein is known to increase SPAK and OSR1 activity. Dr. Mehellou showed that the binding of SPAK and OSR1 proteins to MO25 is mediated by a serine phosphorylation site on SPAK and OSR1, which acts as a ‘key’ and docks into a pocket ‘lock’ that is present on MO25. Indeed, the phosphorylation of SPAK and OSR1 at this highly conserved serine site improves the binding affinity to MO25, which translates into higher activation of SPAK and OSR1. The study also showed that this serine phosphorylation involves the WNK kinases, which are mutated in hypertension. Further reported experiments mapped the site on MO25 that binds the phosphoserine region of SPAK and OSR1.

In the second study, Dr. Mehellou and colleagues discovered a clinically used drug known as Verteporfin (VisudyneÔ) as a potent inhibitor of SPAK and OSR1. This was an important finding as the inhibition of SPAK and OSR1 kinases has been shown to lead to a lowering of blood pressure. Several studies are pursuing the development of Verteporfin as an anticancer agent, so the study by Dr. Mehellou sheds the light on possible lowering of blood pressure as a side effect of this drug. The study also provides an explanation for the fluctuation in blood pressure that was observed in living organisms treated with Verteporfin.

Together these two studies provide important insights into the regulation of SPAK and OSR1 and its implications on the regulation of blood pressure. Additionally, these studies will facilitate the discovery of novel drugs that target SPAK and OSR1 and be effective treatments for hypertension.

The two studies can be found here and here.

 

Cardiff University

 


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