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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]
SLC25 family of mitochondrial transporters in GtoPdb v.2025.3
Get PDFMitochondrial carriers are nuclear-encoded proteins, which translocate solutes across the inner mitochondrial membrane. Mitochondrial carriers are functional as monomers and have six TM alpha-helices and the termini in the mitochondrial intermembrane space
SLC8 family of sodium/calcium exchangers in GtoPdb v.2025.3
No full textThe sodium/calcium exchangers (NCX) use the extracellular sodium concentration to facilitate the extrusion of calcium out of the cell. Alongside the plasma membrane Ca2+-ATPase (PMCA) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA), as well as the sodium/potassium/calcium exchangers (NKCX, SLC24 family), NCX allow recovery of intracellular calcium back to basal levels after cellular stimulation. When intracellular sodium ion levels rise, for example, following depolarisation, these transporters can operate in the reverse direction to allow calcium influx and sodium efflux, as an electrogenic mechanism. Structural modelling suggests the presence of 9 TM segments, with a large intracellular loop between the fifth and sixth TM segments [1]
SLCO family of organic anion transporting polypeptides in GtoPdb v.2025.3
Get PDFThe SLCO superfamily is comprised of the organic anion transporting polypeptides (OATPs). The 11 human OATPs are divided into 6 families and ten subfamilies based on amino acid identity. These proteins are located on the plasma membrane of cells throughout the body. They have 12 TM domains and intracellular termini, with multiple putative glycosylation sites. OATPs mediate the sodium-independent uptake of a wide range of amphiphilic substrates, including many drugs and toxins. Due to the multispecificity of these proteins, this guide lists classes of substrates and inhibitors for each family member. More comprehensive lists of substrates, inhibitors, and their relative affinities may be found in the review articles listed below
Cyclooxygenase in GtoPdb v.2025.3
Get PDFProstaglandin (PG) G/H synthase, most commonly referred to as cyclooxygenase (COX, (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate,hydrogen-donor : oxygen oxidoreductase) activity, catalyses the formation of PGG2 from arachidonic acid. Hydroperoxidase activity inherent in the enzyme catalyses the formation of PGH2 from PGG2. COX-1 and -2 can be nonselectively inhibited by ibuprofen, ketoprofen, naproxen, indomethacin and paracetamol (acetaminophen). PGH2 may then be metabolised to prostaglandins and thromboxanes by various prostaglandin synthases in an apparently tissue-dependent manner
Type II RTKs: Insulin receptor family in GtoPdb v.2025.3
Get PDFThe circulating peptide hormones insulin and the related insulin-like growth factors (IGF) activate Class II receptor tyrosine kinases [13], to evoke cellular responses, mediated through multiple intracellular adaptor proteins. Unlike other receptor tyrosine kinases, the functional receptor in the insulin receptor family is derived from a single gene product, cleaved post-translationally into two peptides, which then cross-link via disulphide bridges to form a heterotetramer. Intriguingly, the endogenous peptide ligands are formed in a parallel fashion with post-translational processing producing a heterodimer linked by disulphide bridges. Signalling through the receptors is mediated through a rapid autophosphorylation event at intracellular tyrosine residues, followed by recruitment of multiple adaptor proteins, notably IRS1 (P35568), IRS2 (Q9Y4H2), SHC1 (P29353), GRB2 (P62993) and SOS1 (Q07889).Serum levels of free IGFs are kept low by the action of IGF binding proteins (IGFBP1-5, P08833, P18065, P17936, P22692, P24593), which sequester the IGFs; overexpression of IGFBPs may induce apoptosis, while IGFBP levels are also altered in some cancers
Type X RTKs: HGF (hepatocyte growth factor) receptor family in GtoPdb v.2025.3
Get PDFThe hepatocyte growth factor (HGF) receptor family - MET and Ron - regulate maturation of the liver in the embryo, as well as having roles in the adult, for example, in the innate immune system. HGF is synthesized as a single gene product, which is post-translationally processed to yield a heterodimer linked by a disulphide bridge. The maturation of HGF is enhanced by a serine protease, HGF activating complex, and inhibited by HGF-inhibitor 1, a serine protease inhibitor. MST1, the ligand of Ron, is two disulphide-linked peptide chains generated by proteolysis of a single gene product
Type XII RTKs: TIE family of angiopoietin receptors in GtoPdb v.2025.3
Get PDFThe TIE family were initially associated with formation of blood vessels (angiogenesis). Endogenous ligands are angiopoietin-1, angiopoietin-2, and angiopoietin-4. angiopoietin-2 appears to act as an endogenous antagonist of angiopoietin-1 function, thus blocking TIE2-mediated signalling. Due to roles in blood vessel formation, monoclonal antibodies are being developed against the ligand Ang2 (cyamemazine57) or a bispecific antibody against VEGF and Ang2 (faricimab) for the treatment of ocular diseases
Receptor tyrosine phosphatase (RTP) family in GtoPdb v.2025.3
Get PDFReceptor tyrosine phosphatases (RTP)- also referred to as receptor-type tyrosine-protein phosphatases (PTPR) - are cell-surface proteins with a single TM region and intracellular phosphatase activity at phosphorylated tyrosine residues. There are 20 family members of classic RPTPs. Many family members exhibit constitutive activity upon heterologous expression, dephosphorylating intracellular targets such as Src tyrosine kinase (SRC) to activate signalling cascades. Family members bind components of the extracellular matrix or cell-surface proteins indicating a role in intercellular communication
Type XIV RTKs: RET in GtoPdb v.2025.3
Get PDFThe RET (REarranged during Transfection) receptor is a transmembrane tyrosine kinase enzyme enzyme. RET forms a complex with members of the GPI-linked GDNF family receptors (GFR) to respond to GDNF family ligands, including glial cell-derived neurotrophic factors including glial cell-derived neurotrophic factor GDNF (211 aa); neurturin (197 aa); artemin (237 aa) and persephin (156 aa). RET also forms a complex with GFRAL, which is activated by growth differentiation factor 15 (GDF15) [25, 35]. RET is involved in neural crest development. Loss of function mutations lead to Hirschprung\u27s disease, while gain of function mutations lead to multiple endocrine neoplasias type 2A and 2B. There are isoforms - RET51 and RET9 - with distinct signalling properties