Biological Function of Prokineticins

Zhou, Qun; Meidan, Rina

doi:10.1007/400_2007_053

Cited by 14 publications

(9 citation statements)

References 91 publications

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“…Expression analysis of PKRs in heterogeneous systems revealed that they bind and are activated by nanomolar concentrations of both recombinant PKs, though PK2 was shown to have a slightly higher affinity for both receptors than was PK1 [12]. Hence, in different tissues, specific signaling outcomes following receptor activation may be mediated by different ligand-receptor combinations, in accordance with the expression profile of both ligands and receptors in that tissue [13]. Activation of PKRs leads to diverse signaling outcomes, including mobilization of calcium, stimulation of phosphoinositide turnover, and activation of the p44/p42 MAPK cascade in overexpressed cells, as well as in endothelial cells naturally expressing PKRs [5], [7], [8], [14], [15] leading to the divergent functions of PKs.…”

Section: Introductionmentioning

confidence: 88%

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

et al. 2011

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Background and MotivationThe Prokineticin receptor (PKR) 1 and 2 subtypes are novel members of family A GPCRs, which exhibit an unusually high degree of sequence similarity. Prokineticins (PKs), their cognate ligands, are small secreted proteins of ∼80 amino acids; however, non-peptidic low-molecular weight antagonists have also been identified. PKs and their receptors play important roles under various physiological conditions such as maintaining circadian rhythm and pain perception, as well as regulating angiogenesis and modulating immunity. Identifying binding sites for known antagonists and for additional potential binders will facilitate studying and regulating these novel receptors. Blocking PKRs may serve as a therapeutic tool for various diseases, including acute pain, inflammation and cancer.Methods and ResultsLigand-based pharmacophore models were derived from known antagonists, and virtual screening performed on the DrugBank dataset identified potential human PKR (hPKR) ligands with novel scaffolds. Interestingly, these included several HIV protease inhibitors for which endothelial cell dysfunction is a documented side effect. Our results suggest that the side effects might be due to inhibition of the PKR signaling pathway. Docking of known binders to a 3D homology model of hPKR1 is in agreement with the well-established canonical TM-bundle binding site of family A GPCRs. Furthermore, the docking results highlight residues that may form specific contacts with the ligands. These contacts provide structural explanation for the importance of several chemical features that were obtained from the structure-activity analysis of known binders. With the exception of a single loop residue that might be perused in the future for obtaining subtype-specific regulation, the results suggest an identical TM-bundle binding site for hPKR1 and hPKR2. In addition, analysis of the intracellular regions highlights variable regions that may provide subtype specificity.

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Section: Introductionmentioning

confidence: 88%

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

et al. 2011

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“…Prokineticin 2 (PK2) is a multifunctional secreted regulatory peptide that signals through two G protein-coupled receptors termed prokineticin receptors 1 and 2 (PKR1 and PKR2) [12-14]. Emerging evidence indicates that PK2 is also associated with pain perception.…”

Section: Introductionmentioning

confidence: 99%

Prokineticin 2 potentiates acid-sensing ion channel activity in rat dorsal root ganglion neurons

Qiu

Liu

Qiu

et al. 2012

J Neuroinflammation

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BackgroundProkineticin 2 (PK2) is a secreted protein and causes potent hyperalgesia in vivo, and is therefore considered to be a new pronociceptive mediator. However, the molecular targets responsible for the pronociceptive effects of PK2 are still poorly understood. Here, we have found that PK2 potentiates the activity of acid-sensing ion channels in the primary sensory neurons.MethodsIn the present study, experiments were performed on neurons freshly isolated from rat dorsal root ganglion by using whole-cell patch clamp and voltage-clamp recording techniques.ResultsPK2 dose-dependently enhanced proton-gated currents with an EC50 of 0.22 ± 0.06 nM. PK2 shifted the proton concentration-response curve upwards, with a 1.81 ± 0.11 fold increase of the maximal current response. PK2 enhancing effect on proton-gated currents was completely blocked by PK2 receptor antagonist. The potentiation was also abolished by intracellular dialysis of GF109203X, a protein kinase C inhibitor, or FSC-231, a protein interacting with C-kinase 1 inhibitor. Moreover, PK2 enhanced the acid-evoked membrane excitability of rat dorsal root ganglion neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, PK2 exacerbated nociceptive responses to the injection of acetic acid in rats.ConclusionThese results suggest that PK2 increases the activity of acid-sensing ion channels via the PK2 receptor and protein kinase C-dependent signal pathways in rat primary sensory neurons. Our findings support that PK2 is a proalgesic factor and its signaling likely contributes to acidosis-evoked pain by sensitizing acid-sensing ion channels.

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“…Although the role of prokineticin signaling has been elaborated in a number of diverse physiologic processes, including inflammation, haematopoeisis, angiogenesis, circadian rhythms, and reproduction (reviewed in Refs 7,15,16 …”

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confidence: 99%

Increased prokineticin 2 expression in gut inflammation: role in visceral pain and intestinal ion transport

Watson

Lilley

Panesar

et al. 2011

Neurogastroenterology Motil

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Elevated Prok2 levels, as a consequence of gastrointestinal tract inflammation, induce visceral pain via prokineticin receptors. This observation, together with the finding that PROK2 can modulate intestinal ion transport, raises the possibility that inhibitors of PROK2 signaling may have clinical utility in gastrointestinal disorders, such as irritable bowel syndrome and inflammatory bowel disease.

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Biological Function of Prokineticins

Cited by 14 publications

References 91 publications

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

Prokineticin 2 potentiates acid-sensing ion channel activity in rat dorsal root ganglion neurons

Increased prokineticin 2 expression in gut inflammation: role in visceral pain and intestinal ion transport

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