IUPHAR/BPS Guide to Pharmacology CITE
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SLC36 family of proton-coupled amino acid transporters in GtoPdb v.2025.3
Full text linkMembers of the SLC36 family of proton-coupled amino acid transporters are involved in membrane transport of amino acids and derivatives [31, 32]. The four transporters show variable tissue expression patterns and are expressed in various cell types at the plasma-membrane and in intracellular organelles. PAT1 is expressed at the luminal surface of the small intestine and absorbs amino acids and derivatives [4]. In lysosomes, PAT1 functions as an efflux mechanism for amino acids produced during intralysosomal proteolysis [2, 28]. PAT2 is expressed at the apical membrane of the renal proximal tubule [7] and at the plasma-membrane in brown/beige adipocytes [33]. PAT1 and PAT4 are involved in regulation of the mTORC1 pathway [12, 30]. More comprehensive lists of substrates can be found within the reviews under Further Reading and in the references [3]
Type XX RTKs: STYK1 in GtoPdb v.2025.3
Full text linkSimilar to the LMR RTK family, STYK1 has a truncated extracellular domain, but also displays a relatively short intracellular tail beyond the split kinase domain. Also known as NOK, STYK1 has been linked to EGFR signalling [2, 3]
Regulators of G protein Signaling (RGS) proteins in GtoPdb v.2025.3
Full text linkRegulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [226, 530, 579, 584, 585, 744, 755, 445, 11]
5-Hydroxytryptamine receptors in GtoPdb v.2025.3
Full text link5-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [201] and subsequently revised [183]) are, with the exception of the ionotropic 5-HT3 class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [41, 500]. Most 5-HT receptors (except 5-ht1e and 5-ht5b) play specific roles mediating functional responses in different tissues (reviewed by [479, 395])
Calcitonin receptors in GtoPdb v.2025.3
Full text linkThis receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [134, 76, 73]) are generated by the genes CALCR (which codes for the calcitonin receptor, CTR) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 150 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CTR; these in turn produce variants of amylin receptors [134], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin, α-CGRP (formerly known as CGRP-I), β-CGRP (formerly known as CGRP-II), amylin (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin and adrenomedullin 2/intermedin. There are species differences in peptide sequences, particularly for the calcitonins. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CTR but it is not expressed in humans [95]. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. There are several approved drugs that target this receptor family, such as pramlintide, erenumab, and the "gepant" class of CGRP receptor antagonists. There are also species differences in agonist pharmacology; for example, CGRP displays potent activity at multiple rat and mouse receptors [60, 15]. The summary table only reflects human receptor pharmacology
Endothelin receptors in GtoPdb v.2025.3
Full text linkEndothelin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Endothelin Receptors [25]) are activated by the endogenous 21 amino-acid peptides endothelins 1-3 (endothelin-1, endothelin-2 and endothelin-3)
Leukotriene receptors in GtoPdb v.2025.3
Full text linkThe leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [36, 39]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB4 receptor whereas the BLT2 receptor in addition to being a low-affinity LTB4 receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [206] and the vanilloid TRPV1 ligand-gated nonselective cation channel [228]. The crystal structure of the BLT1 receptor was initially determined in complex with selective antagonists [145, 236] and extended to the cryo-electron microscopy structure of LTB4-bound human BLT1 receptor at 2.91 Å resolution [402]. The receptors for the cysteinyl-leukotrienes (i.e. LTC4, LTD4 and LTE4) are termed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. The crystal structures of both receptors have been solved; CysLT1 in complex with zafirlukast and pranlukast [208] and CysLT2 in complex with three dual CysLT1/CysLT2 antagonists [126]. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [39]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y12 receptor [101, 256, 286], GPR17 [60] and the oxoglutarate receptor OXGR1 (previously referred to as GPR99) [177]
Melatonin receptors in GtoPdb v.2025.3
Full text linkMelatonin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Melatonin Receptors [40]) are activated by the endogenous ligands melatonin and clinically used drugs like ramelteon, agomelatine and tasimelteon
Hydroxycarboxylic acid receptors in GtoPdb v.2025.3
Full text linkThe hydroxycarboxylic acid family of receptors (ENSFM00500000271913, nomenclature as agreed by the NC-IUPHAR Subcommittee on Hydroxycarboxylic acid receptors [37, 12]) respond to organic acids, including the endogenous hydroxy carboxylic acids 3-hydroxy butyric acid and L-lactic acid, as well as the lipid lowering agents nicotinic acid (niacin), acipimox and acifran [55, 62, 67]. These receptors were provisionally described as nicotinic acid receptors, although nicotinic acid shows submicromolar potency at HCA2 receptors only and is unlikely to be the natural ligand [62, 67]
Orexin receptors in GtoPdb v.2025.3
Full text linkOrexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [79]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, prepro-orexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [120, 79]. Orexin signaling has been associated with regulation of sleep and wakefulness, reward and addiction, appetite and feeding, pain gating, stress response, anxiety and depression. Currently the orexin receptor ligands in clinical use are the dual orexin receptor antagonists suvorexant, lemborexant and daridorexant, which are used as hypnotics, and several dual, as well as OX1- and OX2-selective antagonists are under development for different indications. Multiple orexin agonists are in development for the treatment of narcolepsy and other sleep disorders. Orexin receptor 3D structures have been solved [150, 148, 55, 130, 47, 113, 7, 149]