Why do you think your paper is highly cited?

The review has probably been cited so much as it covers an area of research that is really just taking off. Study of the PAR family is becoming more popular as the receptors are identified as potentially important in several disease states relating to inflammation, pain and cancer. It also covers a large amount of literature; particularly that dealing with thrombin receptor pharmacology which has been a very active area over the last 10-15 years. This review, for the first time, gives a comprehensive summary of the work carried out on these receptors.

  Does it describe a new discovery or new methodology that's useful to others?

The work describes a novel family of seven transmembrane domain G-protein coupled receptors, the proteinase-activated receptors or PARs. These receptors are activated by a novel mechanism of action reliant upon serine protease mediated cleavage of the N-terminal sequence of the receptor. We try to give a concise and clear explanation of the experiments carried out to establish this mechanism and the subsequent use of molecular methodologies to enable wider study of these receptors and their pharmacology.

  Can you give us some background on this research?

As mentioned above, the receptors in this family are activated by proteolysis of their N-terminal sequences. This proteolytic event gives rise to a new N-terminal sequence which then interacts with the active site of the receptor. The research into these receptors has focussed strongly on platelet aggregation and the role PAR-1 plays in the cardiovascular system, as this receptor is activated by the blood enzyme thrombin. This area is now expanding as PAR-1 has been identified in other body systems. PAR-2 has been identified in several physiological systems, including cardiovascular and respiratory systems and the GI tract. It is activated by both trypsin and mast tryptase, indicating a potential role in inflammation, which has been backed up by the fact that activation of the receptor can lead to the release of cytokines, and indeed cytokines can up-regulate the expression of the receptor. Importantly, these receptors can be activated by synthetic peptides corresponding to the N-terminal sequence after cleavage, and a great deal of work has, and is, being done into developing these peptides as selective agents with a view to the development of selective antagonists.

  Could you summarize the significance of your paper in layman's terms?

The work that we published documents the discovery, investigation of the activation and pharmacology of the PAR family of receptors. These receptors are potentially of great importance in several disease states including cancer, and a comprehensive review of the literature relating to these receptors should help researchers in their search to develop useful drugs that interact with the PARs.

Dr. Scott Macfarlane,
The Plevin Lab,
Dept. of Physiology and Pharmacology,
University of Strathclyde,
Glasgow, Scotland