The Nobel Prize in Chemistry 2012, G protein-coupled receptors, rightly rewarded

In my Letter to the Editor, I would like to catch the attention of the scientists in the Arab world in both life and medical fields on the importance of one of the major cell protein families named G protein-coupled receptors (GPCRs). Indeed, GPCRs represent key cell membrane receptors involved in our physiology and pathophysiology making them potential pharmacological targets. The argument that I would like to use is of course the recent 2012 Nobel Prize in Chemistry awarded to Professors Robert Lefkowitz from the Duke University Medical Center and Brian Kobilka from the Stanford University in the USA (The Nobel Prize in Chemistry, 2012). Indeed, almost 20 years after the first Nobel Prize in Medicine or Physiology was awarded to Alfred G. Gilman and Martin Rodbell in 1994 for their seminal discovery related to GPCRs (The Nobel Prize in Physiology or Medicine, 1994) their GPCRs won the 2012 Nobel Prize in Chemistry for the pioneer works undertaken on GPCR structure, signaling and pharmacology. Consequently, I hope that this brief insight will make the scientists in the world, and particularly those who are operating in the different countries of the Arab world, more sensitive to GPCRs and their related research fields. Indeed, the recent advances in GPCRs should have a real impact on the Arab researchers and academicians hopefully encouraging them to have another view particularly in terms of teaching, studying, and investigating GPCRs. In my opinion, the academic programs proposed to students in different colleges and departments (medicine, pharmacy, biology, and chemistry) are to some extent poor with respect to GPCRs and their biology and chemistry. Similarly, the research projects tend to ignore this super family of cell surface receptors. This seems to be true for the projects which are related to cancer, diabetes and other major disorders in the endocrine and nervous systems given that some of these disorders including diabetes are reported to present an increasing incidence in this region of the world (The International Diabetes Federation Diabetes Atlas, 2011). Thus, the research projects on GPCRs may cover the genetic/genomic/clinical investigations and experimental as well as molecular pharmacology. In addition, the fundamental research on GPCRs may constitute a promising field of research which consists of structure–function and biochemical studies using new innovative technologies that could be transferred through international collaborations.

The importance of GPCRs resides in the fact that they constitute the largest cell surface protein family (1–3% of the human genes and ∼900 receptors identified) involved in 80% of signaling through the plasma membrane of our cells. Moreover, GPCRs are known to regulate the major biological functions such as neurotransmission, secretion, contraction, cell growth and migration (Bockaert and Pin, 1999; Fredriksson et al., 2003). This diversity of GPCR action is in fact linked to the diversity of stimuli known to activate these receptors including light, odorants, nucleotides, peptides, neurotransmitters, and protein hormones (Bockaert and Pin, 1999; Fredriksson et al., 2003). Interestingly, the importance of GPCRs is illustrated by their well established implication in diverse pathologies such as neurological disorders, cardiovascular diseases, cancer, allergies, and diabetes (Insel et al., 2007; Spiegel and Lee, 2004). Also GPCRs have been reported to constitute an important molecular constituent used by certain pathogens during the infection process (Coureuil et al., 2010). Thus, because of their central role in pathology GPCRs present a particular interest for the pharmaceutical farms since they are the target of about 50% of the drugs used nowadays in medicine (Esbenshade, 2006).

Since the discovery of the key element involved in GPCR function and signaling (i.e. G proteins and cAMP) in 70–80’s (Rodbell et al., 1969), which led the Nobel Prize in Medicine or Physiology to be shared between Alfred G. Gilman and Martin Rodbell in 1994 (The Nobel Prize in Physiology or Medicine, 1994), and for the cloning of the first GPCR which is β-adrenergic receptor in 1986 (Dixon et al., 1986), GPCRs continue to be the center of intense investigation and research in both academic and pharmaceutical laboratories. As a result, considerable progresses have been reached such as the crystal structure of rhodopsin in 2000 (Palczewski et al., 2000) and later on that of various GPCRs (bound or not with their selective ligands and G proteins) obtained by Kobilka’s group (Granier and Kobilka, 2012), and many new intriguing concepts have emerged such as oligomerization, G protein-independent signaling, and biased signaling (Eglen et al., 2007). For instance, GPCR oligomerization constitutes one of the major revolutionary advances of the last decade since it is now evident that these transmembrane proteins can form homo- (between identical receptor proteins) and heteromer (between different receptor proteins) complexes with specific pharmacological, biological, and biochemical properties (Devi, 2001). Interestingly, such specific properties might open new therapeutic perspectives to treat human diseases such as neurodegenerative and neuropsychiatric diseases since GPCR heteromers represent potential drug targets (Franco, 2009). Consequently, the research on GPCR oligomers, especially heteromers, constitutes a very attractive field of research as illustrated by the increasing number of scientific publications on GPCR oligomerization. Moreover, for a long time GPCRs were named to have been thought to trigger cell signaling only via the interaction with and activation of another major cell protein family, the heterotrimeric G proteins. However, many recent studies including those reported by Professor Robert Lefkowitz have shown that GPCRs also mediate signaling via diverse pathways involving various intracellular proteins independently on the heterortimeric G proteins (i.e. arrestins, src, and tyrosine kinase) (Lefkowitz and Shenoy, 2005). This diversity and multiplicity in GPCR signaling further demonstrate the complexity of this family of receptors which opens more promising possibilities for research and investigation. Recently, the concept of biased signaling mostly supported by the seminal works from Lefkowitz’s laboratory has emerged in the GPCR field (Whalen et al., 2011; Rajagopal et al., 2010). The biased signaling is in fact tightly linked to the multiple signaling of GPCRs (G protein-dependent and G protein-independent) and it is defined as the property that some ligands/drugs (agonists or antagonists) may have which consists to activate one specific signaling pathway and not others via the activation and/or the stabilization of one specific conformation or state of the targeted receptor. Understanding the biased signaling of GPCRs and their drugs will certainly help the pharmaceutical laboratories to develop new generation of drugs that are more specific, selective, and efficient with fewer side effects. All these findings illustrate the diversity and the complexity of GPCR function emphasizing the importance of updating our knowledge on GPCRs in fundamental, applied, and clinical research and academic programs. In addition, all the recent advances in GPCRs are now pushing the pharmaceutical farms to revise their drug discovery and to better adjust their parameters and standards in the main objective to improve human health.

Finally, I believe that the 2012 Nobel Prize in Chemistry constitutes a “second recognition” of the GPCR field which will certainly open a new area in research on this family of drug targets. Therefore, patricians, academicians and researchers in the Arab world should take part in this new area for the benefit of the local and worldwide populations.