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Transient Receptor Potential Channels and Itch
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Mahar Fatima, Jingyi Liu, Bo Duan
TRPV1 (also known as VR1) is the founding member of thermosensitive TRP channels that enables primary polymodal nociceptors to detect ambient temperature changes (>43°C) (15,17–20). In addition, TRPV1 can be activated by capsaicin, a principal pungent component of peppers, low pH, and numbers of molecules associated with inflammation and tissue damage, such as bradykinin, prokineticin, prostaglandins, anandamide, and retinoids (20–25). TRPV1 majorily marks a population of unmyelinated, slowly conducting neurons (C-nociceptor) that express neuropeptides substance P, neurokinin A, and calcitonin gene-related peptide and constitute approximately 30%–50% of all sensory neurons situated in the rodent sensory ganglia (19,26). TRPV1 functions as a polymodal receptor for noxious heat, pain, and itch (26,27). Previous researches have extensively investigated the functions of TRPV1 in acute and chronic pain. Current evidence suggests that TRPV1 also plays an important role in both acute and chronic itch conditions.
Endocrine Functions of Brain Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The importance of olfactory bulb development to reproduction in humans is exemplified by the phenotype of Kallmann’s syndrome (KS), a genetic disorder classified as hypogonadotropic hypogonadism. Such patients have poorly defined secondary sexual characteristics, are infertile, and are at increased risk of developing osteoporosis. They are distinguished by having either a reduced, or a total loss of the sense of smell. Anosmia in KS patients is due to a perturbed olfactory bulb development, whereas the observed infertility is due to an impaired maturation or defective migration of the GnRH neurons. Mutations in prokineticin genes (PROK1 and PROK2) lead to hypogonadotropic hypogonadism without anosmia, suggesting that factors other than suboptimal migration can also lead to functional deficiencies in GnRH. Table 4.4 summarizes the major features of Kallmann’s syndrome and common treatment options.
The inherited basis of hypergonadotropic hypogonadism
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
The clinical phenotypes of PROKR2/PROK2 mutations, encoding prokineticin receptor-2 and prokineticin-2, respectively, range from both classical KS to normosmic hypogonadotropic hypogonadism.59 Nonreproductive phenotypes include fibrous dysplasia, bimanual synkinesia, and epilepsy. Patients with the more severe reproductive dysfunction tend to have biallelic mutations in PROK2/PROKR2 and fewer associated nonreproductive abnormalities. Patients with monoallelic mutations have less severe reproductive dysfunction and more nonreproductive abnormalities. The PROKR2 is a G protein–coupled receptor that binds to the ligand PROK2. Mouse prok2 knockout models have small, abnormally shaped olfactory bulbs with an accumulation of neurons in the rostral migratory stream (RMS) between the sub-ventricular zone and the olfactory bulb.60
Prokineticin 2 relieves hypoxia/reoxygenation-induced injury through activation of Akt/mTOR pathway in H9c2 cardiomyocytes
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Gang Su, Guangli Sun, Hai Liu, Liliang Shu, Weiwei Zhang, Zhenxing Liang
Prokineticin 2 (PK2), also known as Bv8, is a small chemokine-like secreted protein that exerts its biological activities via activation of two cognate G protein-linked receptors, namely prokineticin receptor 1 (PKR1) and 2 (PKR2) [5]. PK2 is well-documented to be highly expressed in activated immune cells and inflamed murine tissues with infiltrating neutrophils, showing proinflammatory activities via PKR1 [6]. Recent literatures report that PK2 is also implicated in regulating diverse essential physiological and/or pathological processes, including circadian rhythms, neuroprotection, angiogenesis and pain perception [7–10]. More importantly, it was reported that the expression of PK2 and its receptors were decreased in the hearts of end-state heart failure patients [11]. PK2 activated the protein kinase B (Akt) pathway to prevent cardiomyocytes from apoptosis against hypoxic insult [11]. Still, little is known about the effects of PK2 on I/R injury in AMI.
The peripheral blood transcriptome identifies dysregulation of inflammatory response genes in polycystic ovary syndrome
Published in Gynecological Endocrinology, 2018
Nian-Jun Su, Jian Ma, De-Feng Feng, Shuai Zhou, Zi-Tao Li, Wei-Ping Zhou, Hua Deng, Jia-Ying Liang, Xu-Hui Yang, Yue-Mei Zhang, Feng-Hua Liu, Liang Zhang
In the present analysis, several inflammatory molecules were proposed in PCOS. ORM1/2, orosomucoid 1/2, belongs to key acute-phase plasma proteins. Usually, it increases gene expression due to acute inflammation. Therefore, it is classified as an acute phase reactant. Recently, ORM1 and ORM2 mRNA expression levels were identified up-regulation in endometrium from patients with PCOS revealing inflammatory change compared with controls [18]. PROK2, prokineticin 2, is the human paralogue of PROK1. Strong expression of PROK1 has been reported in PCOS, indicating its involvement in this disease entity [19]. MMP25, matrix metallopeptidase (MMP) 25, also is named as MMP20. Proteins of the MMP family can degrade extracellular matrix in normal physiological processes including embryonic development and tissue remodeling, as well as in pathological processes such as PCOS [20,21]. Elevated serum concentrations of MMP2 and MMP9 were found in women with PCOS [22,23]. The dysregulation of MMP25 in PCOS and its pathological role warrant further research. S100A12, S100 calcium binding protein A12, belongs to the S100 family of proteins. RAGE, a receptor of S100A12, was found highly expressed in serum of PCOS patients [24]. Also, mounting evidence has shown that this gene is involved in inflammation and diabetes [25–27]. Taken together, up-regulation of S100A12 may play an important role in the development of PCOS.
Hot-spot analysis for drug discovery targeting protein-protein interactions
Published in Expert Opinion on Drug Discovery, 2018
Mireia Rosell, Juan Fernández-Recio
Thus, the identification of small-molecule inhibitors of PPIs is not an easy task. Known PPI inhibitors do not have high similarity to traditional inhibitors of enzymes and receptors [30], showing physicochemical properties that may violate traditional rules such as the Lipinski’s Rule of Five [88]. The molecular size of known small-molecule inhibitors of PPIs is around 500–900 Da, with Ki values of less than 1 µM. In many cases (e.g. IL-2, HDM2, and HPV E2), this value is in the mid-nanomolar to low-nanomolar range, comparable to the binding affinity of the protein–protein complex [30]. There are currently some small-molecule inhibitors of PPIs in clinical trials, and a few of them have been approved by the US FDA. Table 1 shows small-molecule drugs that are targeting PPIs [89,90]. Considering the difficulties for a potential drug to reach the clinical trials stage, a lot of attention is focused onto drugs that have already passed clinical trials or have been accepted for medical use. The case of Gabapentin is an interesting example of drug repositioning. This drug was originally designed to mimic the chemical structure of neurotransmitter GABA, and was used as a treatment for epilepsy. But later it was found that this drug significantly reduced PKCε translocation by competitively inhibiting the interaction with the pronociceptive peptides bradykinin and prokineticin 2, and it is now widely used to relieve neuropathic pain in patients with amyotrophic lateral sclerosis [91].