Tuesday morning at EB brought us a wonderful session by the 2016 Julius Axelrod award winner in pharmacology, Dr. Paul A. Insel from UC San Diego. Dr. Insel was introduced by colleague Dr. Joan Heller Brown, and gave the audience a brief overlook of his extensive contributions to the field of pharmacology, which include 300 peer reviewed papers and over 150 invited chapters and reviews on the expression of GPCRs in disease. Dr. Insel’s talk, entitled “Lessons from Endogenously Expressed GPCRs: Nature Knows Best!”, began with a tribute to the 1970 Nobel Prize in Physiology or Medicine awards winner Dr. Julius Axelrod. Dr. Axelrod’s life was truly inspiring and attendees were encouraged to read more about it in the book “Apprentice to Genius” by Robert Kanigel.

Getting down to the science, Dr. Insel began by explaining the importance of GPCRs (G-protein coupled receptors) or, as he so eloquently describes them, “nature’s workhorses”. With 5 families of GPCRs and over 800 individual GPCRs currently identified, 128 of which are classified as orphans (without endogenous physiological agonists), they are the most frequent targets of FDA approved drugs. Although the 2012 Nobel Prize in chemistry was awarded for research done on GPCRs, Dr. Insel stressed that this area of research is not a dead field, not by a longshot. Even though they are frequent targets for drugs, due to their tissue selective expression, ability to amplify signaling events, extracellular accessibility, interaction with many chemicals and relative safety, only about 15% have successfully been targeted. His explanation of why he thinks that is was put in rather unique terms, which he referred to as the Rumsfeld matrix: there are things that we know we know (or assumptions as he put it), things that we know that we don’t know (or gaps in our knowledge) and then there are the things that we don’t know that we don’t know (actual discoveries), with the endogenous expression of GPCRs being this “unknown unknown”. He further went on to talk about differential GPCR expression in cardiac myocytes vs. fibroblasts, and how this GPCR difference between healthy and diseased tissue could be used for treatment not only for cardiac fibrosis but in cancer as well. Over 25 cancers have been identified to have increased GPCR expression, and pancreatic ductal adenocarcinoma has 75 different GPCRs, of which GPRC5A, an orphan receptor, is more highly expressed than in healthy pancreatic tissue. This differential expression could be of significant value for the treatment of this cancer of increasing prevalence.

The session then transitioned into the symposium entitled Evolving Insights Regarding GPCRs: Compartmentation, Signaling and Clinical Utility. Speakers included Dr. Tracy Handel of UCSD, Dr. Hemal Patel of UCSD, Dr. Rennolds Ostrom of Chapman University, and Dr. Martin Michael of Johannes Gutenberg University, after which the panel opened for discussion before the end of the session.