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Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
Opioid receptors were known to exist long before the discovery of the opioid peptides. Indeed, it was the discovery of opioid receptors using radioactive ligands that led to the search for the endogenous peptides by Hughes and Kosterlitz.198 The distribution of opioid receptors was mapped before the distribution of the peptides. The opioid receptors are typically divided into three main subtypes: 1) mu (μ) receptors, 2) delta (δ) receptors, and 3) kappa (κ) receptors. More recently, a new receptor related to the opioid receptors was cloned. Because it had a high degree of homology (similarity) to other opioid receptors but was unresponsive to endogenous opioid peptides (enkephalins, endorphins, dynorphins), it was referred to as an orphan receptor. Subsequently, a novel endogenous peptide ligand for the orphan receptor was isolated and sequenced. This peptide appeared to have nociceptive effects (i.e., cause pain) when bound to the orphan receptor. Thus, the ligand was named nociceptin/orphanin FQ. Now, there appears to be a family of these peptides, and they all bind to GPCRs (i.e., Gi/Go).39,207 The functional significance of the nociceptin/orphanin FQ system is not entirely known, but there is interest in developing antagonists for these receptors because they could be useful in the treatment of pain. The receptor for nociception/ophanin FQ (i.e., the fourth subtype of opioid receptor) is called the nociception/orphanin FQ receptor or NOP-R, and it acts to produce pronociception in some regions of the CNS and analgesia in others.58
Genetic and Biological Alterations in Cancer
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
In bladder cancer the EGF system has emerged as an important target for therapy. EGF receptor (also known as Her 1) is over-expressed in a large number of tumors and expression is associated with tumor grade and stage (48). Another member of the EGF receptor family is the Her 2 receptor, which has no known ligand (termed an orphan receptor) but functions by binding as a homodimer to other EGF receptors. Her 2 has been found to be overexpressed in breast cancer and targeting this receptor (by the Her 2 antibody, Herceptin) has emerged as a promising new therapy. Crucially it is primarily effective in tumors that are known to be Her 2 positive. Her 2 is also known to be over-expressed in bladder cancer but to date the benefits of Herceptin in this tumor have not been encouraging (49, 50). Activating mutations of FGFR3 have emerged as a common feature in many bladder cancers. The principal mutation occurs in the extracellular domain, which allows ligand independent dimerization and constitutive activation of the receptor. Intriguingly these mutations are most commonly found in low-grade superficial tumors and are much less apparent in muscle invasive disease. The prognostic significance of FGFR mutations as well as its therapeutic value is currently the subject of much research (51).
Clinical pharmacology: opioids
Published in Pamela E Macintyre, Suellen M Walker, David J Rowbotham, Clinical Pain Management, 2008
David J Rowbotham, Alcira Serrano-Gomez, Anne Heffernan
Attempts to clone the known opioid receptors led to the accidental cloning of a new, previously unidentified opioid-like receptor. This was christened the orphan receptor because no ligand was known at that time.43 However, a year later, the endogenous ligand was discovered simultaneously by two groups, who named the agonist orphanin F/Q (owing to its terminal amino acids) or nociceptin.45, 46 Nociceptin/orphanin FQ (N/OFQ) is a heptadecapeptide cleaved from prepronociceptin and shows similarity to dynorphin A.47 The “orphan” receptor has been given numerous names: ORL-1 (opioid receptor like), NCR (nociceptin receptor), or OP4. However, latest guidelines from IUPHAR recommend that, because of the structural relationship between this receptor and μ, κ, and δ receptors, it should be considered as a nonopioid branch of the opioid family of receptors. They propose the abbreviation NOP for this receptor.48
An overview of the molecular and clinical significance of the angiopoietin system in leukemia
Published in Journal of Receptors and Signal Transduction, 2023
Saeed Zaka Khosravi, Samira Molaei Ramshe, Mehdi Allahbakhshian Farsani, Mohammadreza Moonesi, Faroogh Marofi, Majid Farshdousti Hagh
Tie-1 is another member of the RTKs family. It is proposed as an orphan receptor because no ligand has been specified for it yet. Tie-1 is the heterodimer of Tie-2 in endothelial cells [30] and regulates the function of the Ang–Tie-2 system [87]. Recently, Xu et al. have demonstrated leukocyte cell-derived chemotaxin 2 (LECT2) as a functional ligand of Tie-1, which modulates heterodimerization of Tie-1/Tie-2 and Tie-2 clustering as well [88]. The Tie-1 gene is located on 1p34.2 and encodes a protein similar to the Tie-2 protein structure. This similarity is about 76% amino acid identity in the intracellular domain and 30% in the extracellular domains [9]. The Tie-1 receptor is cleaved in two pieces when influenced by different factors, such as VEGF, TNFα, and metalloprotease. One is a soluble fragment (sTie-1), which is the extracellular domain, and the transmembrane and intracellular domains, which remain attached to Tie-2 [89].
Changes in expression of orphan receptors GPR99 and GPR107 during the development and establishment of hypertension in spontaneously hypertensive rats
Published in Journal of Receptors and Signal Transduction, 2021
Loranda Calderón-Zamora, Adrian Canizalez-Román, Nidia León-Sicairos, Asdrubal Aguilera-Mendez, Fengyang Huang, Enrique Hong, Santiago Villafaña
On the other hand, the orphan receptor GPR107 belongs to another class of 7TM receptors and is a member of the LUSTR family (lung seven-transmembrane receptor) because it has an extracellular domain highly conserved with glycine and arginine residues in its structure, it also has a structure of seven transmembrane domains common in all GPCRs [18]. It has been identified that this receptor is expressed in rats in tissues such as kidney and heart [19,20]. This receptor is located in chromosomal position 9q34.11 in humans, while in rats it is located in the 3p12 region; it also has a homology of 83% in its amino acid sequence between both species and encoding to protein with 600 amino acids in Homo sapiens and 551 in Rattus norvegicus [22]. It is not yet known which endogenous ligand binds to the orphan receptor GPR107 and for this reason, the function of this receptor is also unknown. However, there is evidence that the administration of neuronostatin induces the early expression of this receptor and increases blood pressure in rats. Interestingly, overexpression of GPR107 has been reported in patients with idiopathic pulmonary arterial hypertension, thus we do not rule out that GPR107 could be involved in hypertension [19,21]. Therefore, the evidence suggests that GPR99 and GPR107 receptors could be involved in the regulation of blood pressure and alterations in the expression of these two receptors could be associated with the development of hypertension. For this reason, the aim of this work was to evaluate whether GPR99 and GPR107 receptors participate in the development or establishment of hypertension.
Regulation of brain drug metabolizing enzymes and transporters by nuclear receptors
Published in Drug Metabolism Reviews, 2018
Dan Xu, Songqiang Huang, Hui Wang, Wen Xie
Orphan receptors include true orphan receptors and adopted orphan receptors. An orphan receptor is a receptor that has a significant similarity in structure with other confirmed receptors, but whose endogenous ligands are unknown at the time of receptor cloning. Once the corresponding ligand has been identified, the receptor is called ‘adopted orphan receptor’. The true orphan receptors are those whose endogenous ligands are yet to be found or may not exist based on structural analysis of the receptors (Germain et al. 2006b), such as the nuclear receptor-related-1 protein (Nurr1) and steroidogenic factor-1 (SF-1). Adopted orphan receptors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), vitamin D3 receptor (VDR) and peroxisome proliferator-activated receptors (PPARs), are key factors in the transcriptional regulation of drug metabolizing enzymes and transporters (Chan et al. 2013). Bauer et al. (2004) first reported that P-glycoprotein (P-gp) can be regulated by PXR in the brain capillary of rats. Wang et al. (2010) recently showed that activation of CAR in the brain capillary of rodents can induce the expressions of P-gp, breast cancer-resistant protein (BCRP) and MRP2 through animal experiments and in vitro BBB models. VDR is widely expressed in the BBB and several cell chambers of the brain parenchyma, participating in the regulation of cytochromes P450 3A (CYP3A). PPARα and PPARγ were reported to express in the BBB, macrophages, glial cells and neurons (Chan et al. 2013). In vitro studies confirmed that the PPARα in the brain was involved in the regulation of drug transporters.