Foreword

One may think that studies of G-protein coupled receptors (GPCR) are old-fashioned in the field of pharmacology. For example, the “Lock and Key” concept of GPCR, which has long been considered useful to explain a ligand and receptor interaction for GPCR. The Lock and Key concept is basically, and simply, a single pathway activated by a single ligand from a single receptor with one kind of heterotrimeric G-protein. However, since the discovery of β-arrestin, a new concept/viewpoint has arisen in GPCR signaling, this new concept/viewpoint allows for many- or more-than-one-originated pathway activated from a single receptor.

This special issue provides five interesting reviews and reports of new studies about recent topics of GPCR. Dr. Hitoshi Kurose and Dr. Sang Geon Kim present a review about the new viewpoints of GPCR antagonism. Dr. Masato Mashimo, Dr. Koichiro Kawashima and Dr. Takeshi Fujii present a review of muscarinic acetylcholine receptors in immune system, including the unique nicotinic acetylcholine receptor related to Gq-protein. Aditionally, several biased activities of prostanoids and their receptors are reviewed and discussed. Dr. Masa-aki Ito, Dr. Kazuki Yoshida, Dr. Isao Matsuoka and their colleagues present a new concept that the ligand-stimulated response is influenced by the dominant type of G-protein coupled to each P2Y receptor. Dr. Keijo Fukushima proposes an association between prostanoid EP3 receptors and malignancy of human colorectal cancer by simulation using bigdata in silico analysis.

GPCR is now well-recognized to be differentially activated by each biased ligand dependently/specifically: the ligand-biased signaling pathway. Therefore, they are like the post-office box system, safe-deposit bank box system, and/or delivery locker system in a town; depending on the swiped and/or scanned card key (ligand) through a card reader of the main panel (receptor), the system may open one appropriate/corresponding door of the box or locker (specific signaling) among many boxes or lockers of the same unit system (total signaling). Indeed, some card keys could open multiple doors at the same time. Thus, each GPCR is not recognized as a simple single pathway activated by a single ligand from a single receptor with one kind of heterotrimeric G-protein, known as the Lock and Key concept. However, this concept/viewpoint may lead to the discovery of new/unknown specific biased signaling pathways of well-known GPCR with stimulation by the familiar cognate and/or in some case, unfamiliar non-cognate ligands. Since each ligand is potentially able to evoke and/or inhibit multiple pathways from GPCR, which are more complex than previously considered, it may be difficult to classify each ligand, especially for GPCR, as simply “agonist” or “antagonist” henceforth.