IUPHAR/BPS Guide to Pharmacology CITE
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Aquaporins in GtoPdb v.2025.3
No full textAquaporins and aquaglyceroporins are membrane channels that allow the permeation of water and certain other small solutes across the cell membrane, or in the case of AQP6, AQP11 and AQP12A, intracellular membranes, such as vesicles and the endoplasmic reticulum membrane [16]. Since the isolation and cloning of the first aquaporin (AQP1) [20], 12 additional mammalian members of the family have been identified, although little is known about the functional properties of one of these (AQP12A; Q8IXF9) and it is thus not tabulated. The other 12 aquaporins can be broadly divided into three families: orthodox aquaporins (AQP0,-1,-2,-4,-5, -6 and -8) permeable mainly to water, but for some additional solutes [4]; aquaglyceroporins (AQP3,-7 -9 and -10), additionally permeable to glycerol and for some isoforms urea [14], and superaquaporins (AQP11 and 12) located within cells [12]. Some aquaporins also conduct ammonia and/or H2O2 giving rise to the terms \u27ammoniaporins\u27 (\u27aquaammoniaporins\u27) and \u27peroxiporins\u27, respectively. Aquaporins are impermeable to protons and other inorganic and organic cations, with the possible exception of AQP1, although this is controversial [14]. One or more members of this family of proteins have been found to be expressed in almost all tissues of the body [reviewed in Yang (2017) [27]]. AQPs are involved in numerous processes that include systemic water homeostasis, adipocyte metabolism, brain oedema, cell migration and fluid secretion by epithelia. Loss of function mutations of some human AQPs, or their disruption by autoantibodies further underscore their importance [reviewed by Verkman et al. (2014) [24], Kitchen et al. (2105) [14]]. Functional AQPs exist as homotetramers that are the water conducting units wherein individual AQP subunits (each a protomer) have six TM helices and two half helices that constitute a seventh \u27pseudotransmembrane domain\u27 that surrounds a narrow water conducting channel [16]. In addition to the four pores contributed by the protomers, an additional hydrophobic pore exists within the center of the complex [16] that may mediate the transport through AQP1. Although numerous small molecule inhibitors of aquaporins, particularly APQ1, have been reported primarily from Xenopus oocyte swelling assays, the activity of most has subsequently been disputed upon retesting using assays of water transport that are less prone to various artifacts [5] and they are therefore excluded from the tables [see Tradtrantip et al. (2017) [23] for a review]
Sodium leak channel, non-selective (NALCN) in GtoPdb v.2025.3
No full textThe sodium leak channel, non selective (NALCN) is a member of the family of four-domain voltage-gated cation channels that include voltage-gated sodium (NaV) and calcium (CaV) channels [13, 23]. It possesses distinctive ion selectivity and pharmacological properties compared to these latter ion channels [6, 21]. NALCN, which is insensitive to tetrodotoxin (10 µM), has been proposed to mediate the tetrodotoxin-resistant and voltage-insensitive Na+ leak current (IL-Na) observed in many types of neurone [14]. However, whether NALCN is constitutively active has been challenged [20, 2, 7]. NALCN is widely distributed within the central nervous system and is also expressed in the heart and pancreas specifically, in rodents, within the islets of Langerhans [13, 14]. There is now strong functional and structural evidence indicating that NALCN forms a channelosome with obligatory auxiliary subunits UNC79, UNC80 and FAM155A (also known as NALF1) [6, 3, 12, 24, 10]. NALCN is the pore-forming α subunit, UNC79 and UNC80 are massive HEAT-repeat proteins that form an intertwined anti-parallel superhelical assembly that docks intracellularly onto NALCN. FAM155A forms an extracellular dome that shields extracellular access pathways to the selective filter of NALCN. There is also increasing evidence suggesting that the NALCN-UNC79-UNC80-FAM155A channelosome is modulated by additional auxiliary subunits including G proteins [18] and neuronal SNARE complex proteins [21]. However, there remain many areas of uncertainty surrounding NALCN function.It is worth noting that there is currently no NALCN-specific pharmacology. Inhibitors include multivalent cations (Gd3+, Ca2+, Mg2+, Ba2+, Zn2+) and small molecules (verapamil, 2-APB, DPBA, fluvastatin, L-703,606) [6, 11, 8, 19]
SLC6 neurotransmitter transporter family in GtoPdb v.2025.3
No full textMembers of the solute carrier family 6 (SLC6) of sodium- and (sometimes chloride-) dependent neurotransmitter transporters [32, 2, 23, 76] are primarily plasma membrane located and may be divided into four subfamilies that transport monoamines, GABA, glycine and neutral amino acids, plus the related bacterial NSS transporters [110]. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuTAa, a Na+-dependent amino acid transporter from Aquiflex aeolicus [139] and in several other transporter families structurally related to LeuT [49]
Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family in GtoPdb v.2025.3
No full textThe TAM receptor family, named from the first letter of each of its constituents, respond to growth arrest specific protein 6 and protein S. These ligands are secreted plasma proteins which undergo vitamin K-dependent post-translational modifications generating carboxyglutamate-rich domains which are able to bind to negatively-charged surfaces of apoptotic cells. Members of this RTK family represented a novel structural motif, when originally sequenced
Acid-sensing (proton-gated) ion channels (ASICs) in GtoPdb v.2025.3
No full textAcid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [52, 2, 3]) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and the mammalian bile acid-activated ion channel BASIC [94], previously known as BLINaC [75] and INaC [77]. ASIC subunits contain 2 TM domains and a large extracellular part whose shape resembles that of a hand, as shown by high-resolution structures of chicken and human ASIC1a [49, 43, 7, 101, 100, 81]. They assemble as homo- or heterotrimers to form proton-gated, voltage-insensitive, Na+ permeable, channels that are activated by levels of acidosis occurring in both physiological and pathophysiological conditions with ASIC3 also playing a role in mechanosensation (reviewed in [48, 93, 52, 74, 23]). Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [88], ASIC1b (ASICβ, BNaC2β) [19] and ASIC1b2 (ASICβ2) [83]; note that ASIC1a is also permeable to Ca2+], ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [70, 89, 42] and ASIC2b (MDEG2, BNaC1β) [60]] differ in the first third of the protein. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [87] is one of the most pH-sensitive isoforms (along with ASIC1a) and has the fastest activation and desensitisation kinetics, however can also carry small sustained currents. ASIC4 (SPASIC) evolved as a proton-sensitive channel but seems to have lost this function in mammals [62]. Mammalian ASIC4 does not support a proton-gated channel in heterologous expression systems but is reported to downregulate the expression of ASIC1a and ASIC3 [1, 47, 35, 58, 24]. ASICs channels are primarily expressed in central (ASIC1a, -2a, 2b and -4) and peripheral neurons including nociceptors (ASIC1-3) where they participate in neuronal sensitivity to acidosis. Humans express, in contrast to rodents, ASIC3 also in the brain [28]. ASICs have also been detected in photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3) (ASIC distribution is reviewed in [59, 29, 46]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [36, 54, 104] and of the PNS in mechanoreceptor-neurite transmission [98, 97]. ASIC activation also contributes to cell damage in focal ischemia [95, 73] and autoimmune inflammation (arthritis and multiple sclerosis) [41, 96], as well as neuron activation during seizures and pain [93, 30, 31, 13, 33]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [60, 5, 39, 11]. In general, the known small molecule inhibitors of ASICs are non-selective or partially selective, whereas the venom peptide inhibitors have substantially higher selectivity and potency. Several clinically used drugs are known to inhibit ASICs, however they are generally more potent at other targets (e.g. amiloride at ENaCs, ibuprofen at COX enzymes) [72, 67]. The information in the tables below are for the effects of inhibitors on homomeric channels, for information of known effects on heteromeric channels see the comments below
ABCB subfamily in GtoPdb v.2025.3
No full textThe ABCB subfamily is composed of four full transporters and two half transporters. This is the only human subfamily to have both half and full types of transporters. ABCB1 was discovered as a protein overexpressed in certain drug resistant tumor cells. It is expressed primarily in the blood brain barrier and liver and is thought to be involved in protecting cells from toxins. Cells that overexpress this protein exhibit multi-drug resistance [8, 1]
Chemokine receptors in GtoPdb v.2025.1
Full text linkChemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [459, 458, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibacterials, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n= 28), CXC (also known as α-chemokines; n= 17) and CX3C (n= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (n= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [33]. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [717] and aliases
Apelin receptor in GtoPdb v.2025.3
Full text linkThe apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [73] and subsequently updated [75]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. apelin-36, apelin-13 and [Pyr1]apelin-13 are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) [88]. A second family of peptides discovered independently and named Elabela [13] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [98, 71]. The enzymatic pathways generating biologically active apelin and Elabela isoforms have not been determined but both propeptides include sites for potential proprotein convertase processing [81]. Structure-activity relationship Elabela analogues have been described [65, 90]. The stoichiometry of apelin receptor-heterotrimeric G protein complexes has been studied using cryogenic-electron microscopy [99]. A crystal structure for the apelin receptor in complex with a G protein-biased agonist has been reported [96]
Neuropeptide FF/neuropeptide AF receptors in GtoPdb v.2025.3
Full text linkThe Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (provisional nomenclature [12]), which exhibit high affinities for neuropeptide FF (NPFF, O15130) and RFamide related peptides (RFRP: precursor gene symbol NPVF, Q9HCQ7). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions
Class A Orphans in GtoPdb v.2025.2
Full text linkTable 1 lists a number of putative GPCRs identified by NC-IUPHAR [197], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [153]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.Table 1: Class A orphan GPCRs with putative endogenous ligands GPR3GPR4GPR6GPR12GPR15GPR17GPR20 GPR22GPR26GPR31GPR34GPR35GPR37GPR39 GPR50GPR63GPR65GPR68GPR75GPR84GPR87 GPR88GPR132GPR149GPR161GPR183LGR4LGR5 LGR6MAS1MRGPRDMRGPRX1MRGPRX2P2RY10TAAR2 In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119)