The cysteinyl leukotrienes-leukotriene C4(LTC4), leukotriene D4(LTD4) and leukotriene E4(LTE4)-are important mediators of human bronchial asthma. Pharmacological studies have determined that cysteinyl leukotrienes activate at least two receptors, designated CysLT1 and CysLT2. The CysLT1-selective antagonists, such as montelukast (Singulair), zafirlukast (Accolate) and pranlukast (Onon), are important in the treatment of asthma. Previous biochemical characterization of CysLT1 antagonists and the CysLT1 receptor has been in membrane preparations from tissues enriched for this receptor. Here we report the molecular and pharmacological characterization of the cloned human CysLT1 receptor. We describe the functional activation (calcium mobilization) of this receptor by LTD4 and LTC4, and competition for radiolabelled LTD4 binding to this receptor by the cysteinyl leukotrienes and three structurally distinct classes of CysLT1-receptor antagonists. We detected CysLT1-receptor messenger RNA in spleen, peripheral blood leukocytes and lung. In normal human lung, expression of the CysLT1-receptor mRNA was confined to smooth muscle cells and tissue macrophages. Finally, we mapped the human CysLT1-receptor gene to the X chromosome.

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Regulator of G-protein signaling (RGS) proteins areGTPase activating proteins (GAPs) of heterotrimeric Gproteins that alter the amplitude and kinetics of receptor-promoted signaling. In this study we defined the G-protein ␣-subunit selectivity of purified Sf9 cell-derived R7 proteins, a subfamily of RGS proteins (RGS6, -7, -9, and -11) containing a G␥-like (GGL) domain that mediates dimeric interaction with G␤ 5 . G␤ 5 /R7 dimers stimulated steady state GTPase activity of G␣-subunits of the G i family, but not of G␣ q or G␣ 11 , when added to proteoliposomes containing M2 or M1 muscarinic receptor-coupled G-protein heterotrimers. Concentration effect curves of the G␤ 5 /R7 proteins revealed differences in potencies and efficacies toward G␣-subunits of the G i family. Although all four G␤ 5 /R7 proteins exhibited similar potencies toward G␣ o , G␤ 5 /RGS9 and G␤ 5 /RGS11 were more potent GAPs of G␣ i1 , G␣ i2 , and G␣ i3 than were G␤ 5 /RGS6 and G␤ 5 /RGS7. The maximal GAP activity exhibited by G␤ 5 /RGS11 was 2-to 4-fold higher than that of G␤ 5 /RGS7 and G␤ 5 /RGS9, with G␤ 5 /RGS6 exhibiting an intermediate maximal GAP activity. Moreover, the less efficacious G␤ 5 /RGS7 and G␤ 5 /RGS9 inhibited G␤ 5 / RGS11-stimulated GTPase activity of G␣ o . Therefore, R7 family RGS proteins are G i family-selective GAPs with potentially important differences in activities.Heterotrimeric guanine nucleotide-binding proteins (G-proteins) act as molecular switches in multiple GPCR 1 signaling pathways via regulation of specific effector molecules such as phospholipase C and adenylyl cyclase. The biological activity of G-protein ␣-subunits is determined by the identity of the bound guanine nucleotide (GTP or GDP), which in turn is governed by the relative rates of guanine nucleotide exchange and hydrolysis of GTP by the intrinsic GTPase activity of G␣-subunits.These opposing reactions are stimulated by agonist-occupied GPCR and GTPase-activating proteins (GAPs).Although some effector proteins exhibit GAP activity (1-3), the primary regulators of GTPase activity of G␣-subunits are a diverse family of regulator of G-protein signaling (RGS) proteins that act as GAPs for heterotrimeric G-protein ␣-subunits (4 -7). This family is defined by a conserved RGS domain, which markedly increases the rate of GTP hydrolysis by G␣-subunits and terminates effector activation by both G␣-and G␤␥-subunits. More than 30 RGS proteins have been identified and organized into subfamilies based on sequence similarity and domain structure. These families vary in size and complexity, from the R4 family whose structure is largely limited to the RGS domain to the R12 and RhoGEF families whose members are large multifunctional proteins containing several domains (for reviews see Refs. 8 -10).The R7 RGS family is a unique multidomain family, which consists of RGS proteins containing a novel G-␥-like (GGL) domain homologous to the G␥-subunit of heterotrimeric Gproteins (11). This domain, found in the mammalian proteins RGS6, -7, -9, and -11 and the Caenorhabdi...

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15537. In addition to this overview, in which are identified ‘Other protein targets’ which fall outside of the subsequent categorisation, there are six areas of focus: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Lysophosphatidic acid (LPA) is an extracellular signaling mediator with a broad range of cellular responses. Three G-protein-coupled receptors (Edg-2, -4, and -7) have been identified as receptors for LPA. In this study, the ectophosphatase lipid phosphate phosphatase 1 (LPP1) has been shown to down-regulate LPAmediated mitogenesis. Furthermore, using degradationresistant phosphonate analogs of LPA and stereoselective agonists of the Edg receptors we have demonstrated that the mitogenic and platelet aggregation responses to LPA are independent of Edg-2, -4, and -7. Specifically, we found that LPA degradation is insufficient to account for the decrease in LPA potency in mitogenic assays, and the stereoselectivity observed at the Edg receptors is not reflected in mitogenesis. Additionally, RH7777 cells, which are devoid of Edg-2, -4, and -7 receptor mRNA, have a mitogenic response to LPA and LPA analogs. Finally, we have determined that the ligand selectivity of the platelet aggregation response is consistent with that of mitogenesis, but not with Edg-2, -4, and -7.The structurally simple phospholipid lysophosphatidic acid (LPA, 1 1-acyl, 2-hydroxy-sn-glycerol-3-phosphate) has been shown in the past decades to mediate an array of biological responses that is anything but simple. LPA has been shown to signal such vital cellular events as mitogenesis (1), platelet aggregation (2), tumor cell invasion (3), and escape from apoptosis (4). LPA is present in serum at low (1-20 M) micromolar concentrations (5) and is produced and released by stimulated platelets (6). The autocrine activation of platelet aggregation, coupled with LPA's mitogenic effects on smooth muscle cells (7) and fibroblasts (8), suggests a functional role for LPA as a wound-healing hormone (see review (9)). Furthermore, LPA accumulates to high concentrations in ovarian cancer ascitic fluid and is mitogenic to ovarian cancer cells, implicating LPA as a marker and mediator of ovarian cancer progression (10).In Recently, specific G-protein-coupled receptors for LPA have been identified within a cluster of eight related receptors termed the Edg (Endothelial differentiation gene) cluster. To date, eight members of the Edg cluster have been described. Edg-2 (15, 19), -4 (20), and -7 (21, 22) have been shown to be LPA receptors and Edg-1 (23, 24), -3, -5 (25), -6 (26, 27), and -8 (28) are receptors for the structurally related phospholipid sphingosine 1-phosphate. The LPA receptors differ with respect to distribution and G-protein coupling. Edg-2 is widely expressed, with highest mRNA levels appearing in brain (20), reflecting expression in Schwann cells and oligodendrocytes (29,30). Edg-4 is most highly expressed in testis and leukocytes (20), whereas Edg-7 is very highly expressed in kidney and prostate (21,22). When stably transfected into the LPA-unresponsive cell line RH7777 (Rat Hepatoma), Edg-2 mediates inhibition of cAMP accumulation, whereas Edg-4 and Edg-7 mediate calcium mobilization (22). Because only the inhibition of cAMP accumulation is pertus...