Every year, with the month of October, comes the excitement of the Nobel session to the global scientific community. In the first few weeks of the month, the Royal Swedish Academy of Sciences and the Nobel Assembly at the Karolinska Institute announce the winners of the Nobel prizes in Physics, Chemistry, and Physiology or Medicine, the most recognizable awards for the impact of scientific work carried out by scientists in these three fields. This recognition also acknowledges the relative importance of a particular scientific area received from the scientific community and the perceived impact the finding has had on human scientific progress. Therefore, the presentation of 10 or more Nobel prizes highlights the importance of research work on the GPCR-mediated signal transduction garnered in the human scientific enterprise.
The first Nobel prize that can be attributed to work related to GPCR-mediated signaling was the 1947 Nobel Prize in Physiology or Medicine, awarded to Carl Ferdinand Cori, Gerty Theresa Cori (née Radnitz), and Bernardo Alberto Houssay for their discoveries related to how glycogen is broken down to glucose and resynthesized in the body for use as a store and source of energy. Through their Nobel prize-winning work, the Coris found that adrenaline, a nonselective agonist for all types of adrenergic receptors, decreases the amount of glycogen in the liver and muscles. [1-6] Houssay received this honor for his discoveries concerning the role of the various hormones, including adrenaline secreted from the anterior pituitary lobe, in carbohydrate metabolism and the onset of diabetes.
In 1967, the Nobel Prize in Physiology or Medicine was awarded jointly to Ragnar Arthur Granit, Haldan Keffer Hartline, and George David Wald for their discoveries concerning the primary physiological and chemical visual processes in the eye.[7–11] Through Nobel prize-winning research work, Wald made important discoveries on the role that the class-A archetypical GPCR rhodopsin plays in scoptic vision and night blindness.
In 1970, the Nobel Prize in Physiology or Medicine was awarded to Julius Axelrod, Bernard Katz, and Ulf Svante von Euler for their work on the release and reuptake of neurotransmitters in neural communication.[12–17] Katz's scientific studies involved the release of the neurotransmitter acetylcholine, whereas the studies by Axelrod and von Euler focused on the neurotransmitter norepinephrine. Norepinephrine exerts its effects by binding to α- and β-adrenergic receptors, while acetylcholine binds to nicotinic acetylcholine receptors and muscarinic acetylcholine receptors.[18]
The 1971 Nobel Prize in Physiology or Medicine went to Earl Wilbur Sutherland Jr for discovering the key role of adenylate cyclase, which produces the archetypical secondary messenger cyclic AMP (cAMP), plays in cellular signaling.[20,21] Adenylate cyclase is a major component of the downstream signaling cascade of the cAMP signal pathway, one of the two principal signal transduction pathways associated with GPCRs mediated signaling.[19–23]
The 1988 Nobel Prize in Physiology or Medicine went to George Herbert Hitchings, Sir James Whyte Black, and Gertrude Belle Elion for their discoveries of important principles for drug treatment.[24–30] Black was particularly interested in developing drugs that targeted GPCRs and was credited with discovering propranolol, an antagonist for ß-adrenergic receptors, and cimetidine, an antagonist for histamine H2 receptor.[31,32]
The 1992 Nobel Prize in Physiology or Medicine was awarded to Edwin Gerhard Krebs and Edmond Henri Fischer for describing how reversible phosphorylation works as a switch to activate proteins and to regulate various cellular processes, including glycogenolysis.[33–39] In their work, the duo further investigated the work of Gerty Cori and Carl Cori on carbohydrate metabolism. Incidentally, phosphorylation is a key regulatory mechanism employed in the GPCR-mediated signal transduction, where signaling of most GPCRs via the G-protein-dependent pathway is terminated by the phosphorylation of active receptors by specific kinases. Moreover, the G protein-independent pathway is mainly regulated by arrestin, which recognizes and binds phosphorylated GPCRs.
The 1994 Nobel Prize in Physiology or Medicine was awarded to Alfred Goodman Gilman and Martin Rodbell for their discovery of G-proteins and the role of these proteins in signal transduction in cells.[40–46] In his work, Rodbell demonstrated that signal transduction through the cell membrane involves a cooperative action of three different functional entities: (1) a discriminator or receptor, which binds the primary messenger, (2) a transducer that requires GTP, and (3) an amplifier that generates large quantities of a second messenger. Gilman discovered that the transducer component of signal transduction that requires GTP is G-protein and was the first to isolate it through his work on leukemia cells. G protein-dependent signaling is the most well-known mechanism employed in GPCRs mediated signal transduction.[47]
The 2000 Nobel Prize in Physiology or Medicine went to Eric Richard Kandel, Arvid Carlsson, and Paul Greengard for research on signal transduction in the nervous system.[48–54] Carlsson won the prize for his discovery that dopamine is a neurotransmitter produced in the basal ganglia, a brain region involved in movement control. Dopamine exerts its action in the human nervous system via dopamine receptors and human trace amine-associated receptor 1 (hTAAR1). Greengard was recognized for his contributions to the elucidation of the signaling pathways by which neurotransmitters such as dopamine, noradrenaline, and serotonin control neuronal excitability.[55,56] He identified a number of signal transduction proteins, particularly kinases and phosphatases, that are involved in synaptic transmission[55,56] Kandel was honored for demonstrating that cellular signaling events such as ion channel conduction and synaptic neurotransmitter release are involved in "short-term memory", whereas cAMP signaling and new protein synthesis are required for "long-term memory".
The 2004 Nobel Prize in Physiology or Medicine went to Richard Axel and Linda Brown Buck for their work on Class-A olfactory receptors.[57–61] The two jointly carried out work to discover that sensing smell involved a large number of relatively specific olfactory receptors that are structurally similar to rhodopsin. These odorant receptors (ORs) now account for about 60% of all identified human GPCRs.
The most recent Nobel prize awarded for work relevant to GPCR-mediated signaling was the 2012 Nobel Prize in Chemistry to Brian Kent Kobilka and Robert Joseph Lefkowitz for their work on GPCR function.[62–66] Lefkowitz was able to isolate β-adrenergic receptors from tissue samples to carry out the first structure-function characterization studies on GPCRs. Later on, Kobilka joined in with Lefkowitz to identify the shared architecture of the β-adrenergic receptor with that of rhodopsin.[67] In 2011, Kobilka further contributed to the field by obtaining the first X-ray crystal structure of a GPCR bound to its signaling partner (β-adrenergic receptor bound to the partial inverse agonist carazolol).[67]
In spite of these advancements, there is much more to be discovered regarding how GPCRs mediate signaling. Our understanding of how various factors, such as lipid composition, osmotic stress, and allosteric ligands, modulate the conformational dynamics of GPCRs remains crude. Much more need to be uncovered about bias signaling, tissue-specific GPCR activation profiles, compartmentalized GPCR signaling, and location bias.[68–70] Further, our understanding of cross-talk between GPCR-mediated signaling pathways with other cellular signaling pathways, as well as non-signaling roles of GPCRs, such as acting as transcription factors, are still in their infancy. Therefore, we envision that this field will continue to produce high-impact research work that will garner more accolades from the global scientific community and continue to make large scientific discoveries to the improvement of human well-being.[68–72]
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Amazing review, Nipuna. Thank you for this. #gpcr #drgpcr