Identification of Two Prokineticin cDNAs: Recombinant Proteins Potently Contract Gastrointestinal Smooth Muscle
Abstract
The motility of gastrointestinal tract is regulated by classical neurotransmitters, neuropeptides, and humoral agents. Two novel human cDNAs have been cloned based on their sequence similarity to a frog skin secretion protein, Bv8, and a nontoxic protein of mamba snake venom. These human cDNAs encode two secreted proteins of 86 and 81 amino acids. Northern blot hybridization has revealed that these cDNAs are expressed in gastrointestinal tract, particularly the stomach. Recombinant proteins with authentic N-terminal sequences have been produced in Escherichia coli and refolded into functional proteins by careful control of protein aggregation. Mass spectrometry has confirmed the formation of five pairs of disulfide bonds. The refolded recombinant proteins potently contract gastrointestinal smooth muscle with EC(50) values in the subnanomolar range. The contractile effects of the recombinant proteins are specific for gastrointestinal smooth muscle, because they have no effect on vascular or respiratory smooth muscle. To reflect their potent and specific effects on gastrointestinal smooth muscle cells, we have named these recombinant proteins prokineticins. Ligand binding studies with iodinated prokineticin revealed the presence of a high-affinity site in ileal smooth muscle. The displacement of specific binding by GTP gamma S suggests that the prokineticin receptor may belong to the family of G protein-coupled receptors. Experiments with verapamil and nifedipine revealed that calcium influx is essential for the contractile activity of prokineticins on gastrointestinal smooth muscle. In summary, we have identified two novel endogenous regulators of gastrointestinal motility. The availability of recombinant prokineticins should provide novel therapeutic agents for disorders involving impaired gastrointestinal motility.
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“Recently, two cysteine-rich peptides, prokineticin 1 (PK1) and prokineticin 2 (PK2), have been identified and shown to stimulate gastrointestinal smooth muscle contractions (Li et al., 2001).”
BackgroundThe prokineticin receptor‐1 (GPR73) promotes cardiomyocyte survival and angiogenesis
Urayama, K., Guilini, C., Messaddeq, N., Hu, K., Steenman, M., Kurose, H., Ert, G., & Nebigil, C. G. (2007) · The FASEB Journal · doi:10.1096/fj.07-8116com · Cited by 94 · see citing works
“nal motility (3), pain sensitization (7), angiogenesis (2,”
BackgroundRuiz‐Gómez, G., Tyndall, J. D. A., Pfeiffer, B., Abbenante, G., & Fairlie, D. P. (2010) · Chemical Reviews · doi:10.1021/cr900344w · Cited by 94 · see citing works
Potential roles of the prokineticins in reproduction
Maldonado‐Pérez, D., Evans, J., Denison, F. C., Millar, R. P., & Jabbour, H. N. (2007) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2006.12.002 · Cited by 94 · see citing works
“[1] to reflect their functions in inducing specific and potent contractions on the smooth muscle of the gastrointestinal tract.”
InfluentialBullock, C. M., Li, J., & Zhou, Q. (2004) · Molecular Pharmacology · doi:10.1124/mol.65.3.582 · Cited by 94 · see citing works
Self-citationNegri, L., & Ferrara, N. (2018) · Physiological Reviews · doi:10.1152/physrev.00012.2017 · Cited by 94 · see citing works
“(136), searching EST databases for homologies to the predicted coding region of Bv8, identified two human sequences, one encoding a protein of 86 amino acids which showed a high degree of homology with VPRA/ MIT1 and the other encoding an 81-amino acid protein highly related to Bv8.”
BackgroundProkineticin 2 and circadian clock output
Zhou, Q., & Cheng, M. (2005) · FEBS Journal · doi:10.1111/j.1742-4658.2005.04984.x · Cited by 92 · see citing works
“Prokineticins and their nonmammalian counterparts exhibit conservation in their amino acid sequences including the first six amino acids in the N-terminal domain (AVITGA) and the 10 cysteine residues predicted to form five pairs of disulfide bonds [20] (Fig.”
InfluentialSelf-citationVascular morphogenesis in the primate ovary
Fraser, H. M., & Duncan, W. C. (2005) · Angiogenesis · doi:10.1007/s10456-005-9004-y · Cited by 91 · see citing works
“Here, it was named prokineticin-1 (PK-1), because it was found to be a potent inducer of smooth muscle contraction [23].”
BackgroundInduction of Bv8 Expression by Granulocyte Colony-stimulating Factor in CD11b+Gr1+ Cells
Qu, X., Zhuang, G., Yu, L., Meng, G., & Ferrara, N. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.326801 · Cited by 90 · see citing works
Nociceptive sensitization by the secretory protein Bv8
Negri, L., Lattanzi, R., Giannini, E., Metere, A., Colucci, M., Barra, D., Kreil, G., & Melchiorri, P. (2002) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704995 · Cited by 88 · see citing works
“Nociceptive sensitization by the secretory protein Bv8 *,1Lucia Negri, 1Roberta Lattanzi, 1Elisa Giannini, 1Alessio Metere, 1Mariantonella Colucci, 2Donatella Barra, 3GuÈ nther Kreil & 1Pietro Melchiorri 1Department of Human Physiology and Pharmacology ``V. Erspamer'', University ``La Sapienza'', 00185 Rome, Italy; 2D…”
MethodInfluentialInsight into the sialome of the castor bean tick, Ixodes ricinus
Chmelař, J., Anderson, J. M., Mu, J., Jochim, R. C., Valenzuela, J. G., & Kopecký, J. (2008) · BMC Genomics · doi:10.1186/1471-2164-9-233 · Cited by 88 · see citing works
“Astakin was shown to be an important hematopoietic cytokine in invertebrates [57] and prokineticin can induce intestinal contraction in mammals [58].”
Cytokine properties of prokineticins
Monnier, J., & Samson, M. (2008) · FEBS Journal · doi:10.1111/j.1742-4658.2008.06559.x · Cited by 87 · see citing works
The epicardium in cardiac repair: From the stem cell view
Limana, F., Capogrossi, M. C., & Germani, A. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.09.002 · Cited by 86 · see citing works
New understandings of the genetic basis of isolated idiopathic central hypogonadism
Bonomi, M., Libri, D. V., Guizzardi, F., Guarducci, E., Maiolo, E., Pignatti, E., Asci, R., & Persani, L. (2011) · Asian Journal of Andrology · doi:10.1038/aja.2011.68 · Cited by 84 · see citing works
Chaly, A. L., Srisai, D., Gardner, E. E., & Sebag, J. A. (2016) · eLife · doi:10.7554/elife.12397 · Cited by 83 · see citing works
“…physiological functions including energy expenditure (Zhou et al., 2012), insulin sensitivity (Dormishian et al., 2013), gastrointestinal contraction (Li et al., 2001), nociception (Negri and Lattanzi, 2011), cardiovascular function and angiogenesis (Boulberdaa et al., 2011; Urayama et al., 2007).”
BackgroundUrayama, K., Guilini, C., Türkeri, G., Takır, S., Kurose, H., Messaddeq, N., Dierich, A., & Nebigil, C. G. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.162404 · Cited by 81 · see citing works
“The first target of cardiomyocyte-PKR1-mediated paracrine regulation is prokineticin-2 itself, for the following reasons: (1) in the TG hearts, prokineticin-2 levels were upregulated; (2) overexpressing PKR1 in H9c2 cells upregulates prokineticin-2 levels in PKR1-level-dependent manner; (3) ablation of PKR1 in mice do…”
BackgroundProsser, H. M., Bradley, A., & Caldwell, M. A. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05958.x · Cited by 77 · see citing works
“To date several physiological roles have been attributed to the prokineticins and their receptors: most notably gut motility (Li et al., 2001), reproductive function (Matsumoto et al., 2006; Maldonado-Perez et al., 2007) and circadian output from the suprachiasmatic nuclei (Cheng et al., 2002; Li…”
BackgroundInfluentialCharacterization and Regulation of Bv8 in Human Blood Cells
Zhong, C., Qu, X., Tan, M., Meng, Y. G., & Ferrara, N. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-1954 · Cited by 79 · see citing works
EG-VEGF: a key endocrine factor in placental development
Brouillet, S., Hoffmann, P., Feige, J., & Alfaidy, N. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.05.006 · Cited by 77 · see citing works
Shaw, J. L. V., Wills, G. S., Lee, C., Horner, P., McClure, M. O., Abrahams, V. M., Wheelhouse, N., Jabbour, H. N., Critchley, H., Entrican, G., et al. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2010.11.019 · Cited by 78 · see citing works
Divergent roles of prokineticin receptors in the endothelial cells: angiogenesis and fenestration
Guilini, C., Urayama, K., Türkeri, G., Dedeoglu, D. B., Kurose, H., Messaddeq, N., & Nebigil, C. G. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00898.2009 · Cited by 73 · see citing works
EG-VEGF and Bv8: a novel family of tissue-restricted angiogenic factors
Ferrara, N., LeCouter, J. E., Lin, R., & Peale, F. V., Jr. (2003) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2003.07.001 · Cited by 72 · see citing works
Kisliouk, T., Levy, N., Hurwitz, A., & Meidan, R. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030492 · Cited by 72 · see citing works
Samson, M., Peale, F. V., Jr., Frantz, G. D., Rioux-Leclercq, N. C., Meyts, E. R., & Ferrara, N. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-032024 · Cited by 71 · see citing works
PROK2/PROKR2 Signaling and Kallmann Syndrome
Dodé, C., & Rondard, P. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00019 · Cited by 71 · see citing works
“PROK1 has 80% sequence identity with MIT1 and 58% identity with PROK2 (Li et al., 2001).”
BackgroundInfluentialProkineticin 2 Is a Hypothalamic Neuropeptide That Potently Inhibits Food Intake
Gardiner, J., Bataveljic, A., Patel, N. A., Bewick, G. A., Roy, D., Campbell, D., Greenwood, H. C., Murphy, K. G., Hameed, S., Jethwa, P. H., et al. (2009) · Diabetes · doi:10.2337/db09-1198 · Cited by 66 · see citing works
“The prokineticins are so called because the first effect ascribed to them was the stimulation of guinea pig ileum smooth muscle contraction (2).”
Triazine Compounds as Antagonists at Bv8-Prokineticin Receptors
Balboni, G., Lazzari, I., Trapella, C., Negri, L., Lattanzi, R., Giannini, E., Nicotra, A., Melchiorri, P., Visentin, S., Nuccio, C. D., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800854e · Cited by 66 · see citing works
Bv8, the amphibian homologue of the mammalian prokineticins, modulates ingestive behaviour in rats
Negri, L., Lattanzi, R., Giannini, E., Felice, M. D., Colucci, A., & Melchiorri, P. (2004) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705686 · Cited by 65 · see citing works
Kimball, E. S., Prouty, S., Pavlick, K. P., Wallace, N. H., Schneider, C. R., & Hornby, P. J. (2007) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2007.00939.x · Cited by 63 · see citing works
Variations inPROKR2, But NotPROK2, Are Associated With Hypopituitarism and Septo-optic Dysplasia
McCabe, M. J., Gaston‐Massuet, C., Gregory, L. C., Alatzoglou, K. S., Tziaferi, V., Sbai, O., Rondard, P., Masumoto, K., Nagano, M., Shigeyoshi, Y., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3067 · Cited by 60 · see citing works
Cotinine Exposure Increases Fallopian Tube PROKR1 Expression via Nicotinic AChRα-7
Shaw, J. L. V., Oliver, E., Lee, C., Entrican, G., Jabbour, H. N., Critchley, H., & Horne, A. W. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.100243 · Cited by 61 · see citing works
Prokineticin 2 is an endangering mediator of cerebral ischemic injury
Cheng, M., Lee, A. G., Culbertson, C. J., Sun, G.-H., Talati, R. K., Manley, N. C., Li, X., Zhao, H., Lyons, D. M., Zhou, Q., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113363109 · Cited by 63 · see citing works
Self-citationProkineticin-2, motilin, ghrelin and metoclopramide: Prokinetic utility in mouse stomach and colon
Bassil, A. K., Dass, N. B., Murray, C. D., Muir, A. I., & Sanger, G. J. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.09.007 · Cited by 60 · see citing works
“In the present experiments, PK2 had no effects on baseline muscle tension, an observation contrasting with a report that PK1 and PK2 contracted guinea-pig gut muscle, via a tetrodotoxin-resistant mechanism (Li et al., 2001).”
BackgroundResultLight-Dependent Regulation of Sleep and Wake States by Prokineticin 2 in Zebrafish
Chen, S., Reichert, S., Singh, C., Oikonomou, G., Rihel, J., & Prober, D. A. (2017) · Neuron · doi:10.1016/j.neuron.2017.06.001 · Cited by 58 · see citing works
“One of these factors, prokineticin 2 (Prok2), has been implicated in diverse functions, including neurogenesis, angiogenesis, and nociception (Gardiner et al., 2010; LeCouter et al., 2001; Li et al., 2001; Ng et al., 2005).”
LeCouter, J. E., & Ferrara, N. (2003) · Trends in Cardiovascular Medicine · doi:10.1016/s1050-1738(03)00110-5 · Cited by 57 · see citing works
Lambert, C. M., Machida, K. K., Smale, L., Núñez, A. A., & Weaver, D. R. (2005) · Journal of Biological Rhythms · doi:10.1177/0748730405275135 · Cited by 57 · see citing works
“Despite having the paradoxical name of pro-kineticin (for its ability to stimulate intestinal smooth muscle contractility; Li et al., 2001), PK2 is proposed to play a major role in inhibiting locomotor activity during the day in nocturnal species (Cheng et al., 2002).”
BackgroundXin, H., Lu, R. O., Lee, H., Zhang, W., Zhang, C., Deng, J., Liu, Y., Shen, S., Wagner, K., Forman, S. J., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.450049 · Cited by 56 · see citing works
Peßler, F., Mayer, C. T., Jung, S. M., Behrens, E. M., Dai, L., Menetski, J. P., & Schumacher, H. R. (2008) · Arthritis Research & Therapy · doi:10.1186/ar2435 · Cited by 55 · see citing works
“Prokineticins are evolutionary highly conserved small secreted polypeptides that play roles in various tissues, including the central nervous system, the gastrointestinal tract, the haematopoietic system and the vasculature [14,34,35].”
InfluentialBiological activities of Bv8 analogues
Negri, L., Lattanzi, R., Giannini, E., Colucci, M., Mignogna, G., Barra, D., Grohovaz, F., Codazzi, F., Kaiser, A., Kreil, G., et al. (2005) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706376 · Cited by 54 · see citing works
Arachnid toxinology in Australia: From clinical toxicology to potential applications
Nicholson, G. M., Graudins, A., Wilson, H., Little, M., & Broady, K. W. (2006) · Toxicon · doi:10.1016/j.toxicon.2006.07.025 · Cited by 53 · see citing works
“These polypeptides include mamba intestinal toxin 1 (MIT1) from the black mamba Dendroaspis p. polylepis (Boisbouvier et al., 1998), Bv8 a small peptide isolated from skin secretions of the toad Bombina variegata (Mollay et al., 1999), the prokineticin family of proteins (also known as endocrine gland-derived, vascula…”
BackgroundNgan, E., Sit, F. Y. L., Lee, K. L., Miao, X., Yuan, Z., Wang, W., Nicholls, J. M., Wong, K. K., Garcia-Barceló, M., Lui, V. C. H., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2176 · Cited by 53 · see citing works
Curtis, V. F., Wang, H., Yang, P., McLendon, R. E., Li, X., Zhou, Q., & Wang, X. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054916 · Cited by 52 · see citing works
Self-citationSarfati, J., Dodé, C., & Young, J. (2010) · Frontiers of hormone research · doi:10.1159/000312698 · Cited by 51 · see citing works
Impaired Pain Sensation in Mice Lacking Prokineticin 2
Hu, W., Zhang, C., Li, J., Luo, Z. D., Amadesi, S., Bunnett, N. W., & Zhou, Q. (2006) · Molecular Pain · doi:10.1186/1744-8069-2-35 · Cited by 51 · see citing works
Self-citationKisliouk, T., Podlovni, H., Spanel‐Borowski, K., Ovadia, O., Zhou, Q., & Meidan, R. (2005) · Endocrinology · doi:10.1210/en.2005-0297 · Cited by 51 · see citing works
Self-citationMacdonald, L. J., Sales, K. J., Grant, V., Brown, P., Jabbour, H. N., & Catalano, R. D. (2011) · Molecular Human Reproduction · doi:10.1093/molehr/gar031 · Cited by 50 · see citing works
“Prokineticin 1 (PROK1) is a secreted protein previously known as endocrine gland vascular endothelial growth factor (LeCouter et al., 2001; Li et al., 2001).”
Hsiao, C.-Y., & Song, Y.-L. (2009) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2009.10.016 · Cited by 48 · see citing works
“[16] citing angiogenesis [17,18], involvement of reproduction, cancer, neuronal survival and neurogenesis [19e21], influence of gastrointestinalmotility [22], control of circadian rhythm [23,24] and modulation of complex behaviors [25] and so on.”
BackgroundLeCouter, J. E., Lin, R., Frantz, G. D., Zhang, Z., Hillan, K. J., & Ferrara, N. (2003) · Endocrinology · doi:10.1210/en.2002-0146 · Cited by 49 · see citing works
Evidence of prokineticin dysregulation in fallopian tube from women with ectopic pregnancy
Shaw, J. L. V., Denison, F. C., Evans, J., Durno, K., Williams, A. R. W., Entrican, G., Critchley, H., Jabbour, H. N., & Horne, A. W. (2010) · Fertility and Sterility · doi:10.1016/j.fertnstert.2009.10.061 · Cited by 47 · see citing works
Watson, R. P., Lilley, E. J., Panesar, M., Bhalay, G., Langridge, S., Tian, S., McClenaghan, C., Ropenga, A., Zeng, F., & Nash, M. S. (2011) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2011.01804.x · Cited by 46 · see citing works
Franchi, S., Giannini, E., Lattuada, D., Lattanzi, R., Tian, H., Melchiorri, P., Negri, L., Panerai, A. E., & Sacerdote, P. (2008) · BMC Immunology · doi:10.1186/1471-2172-9-60 · Cited by 46 · see citing works
“proteins called prokineticin-1 (PROK 1) or endocrine gland-vascular endothelial growth factor (EG-VEGF), and human Bv8 or PROK 2 [2-4].”
Prokineticin-1: A Novel Mediator of the Inflammatory Response in Third-Trimester Human Placenta
Denison, F. C., Battersby, S., King, A. E., Szuber, M., & Jabbour, H. N. (2008) · Endocrinology · doi:10.1210/en.2007-1695 · Cited by 46 · see citing works
- Authors
- Li, M., Bullock, C. M., Knauer, D. J., Ehlert, F. J., & Zhou, Q. Y.
- Affiliations
- University of California, Irvine (US)
- ORCID
- Zhou, Q. Y.
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2001-04-01
- Volume
- 59
- Issue
- 4
- Pages
- 692-698
- ISSN
- 0026-895X (ISSN-L)
- 1521-0111
- OpenAlex
- W1825488655
- Cited by
- 269
- References
- 36
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 1 · 2023: 12 · 2022: 10 · 2021: 7 · 2020: 8 · 2019: 3 · 2018: 7 · 2017: 7 · 2016: 9 · 2015: 12 · 2014: 10 · 2013: 13 · 2012: 12
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of California, Irvine
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Keywords
- prokineticins, gastrointestinal smooth muscle contraction, gastrointestinal motility, prokineticin receptors, G protein-coupled receptors, disulfide bond formation, recombinant protein refolding, calcium influx, ileal smooth muscle, Bv8, stomach, gastrointestinal motility disorders
- MeSH terms
- Animals, Binding, Competitive, Cloning, Molecular, Dose-Response Relationship, Drug, Gastrointestinal Hormones, Guinea Pigs, Humans, Ileum, Molecular Sequence Data, Muscle, Smooth, Neuropeptides, Organ Specificity, Receptors, Cell Surface, Recombinant Proteins, Guanosine 5'-O-(3-Thiotriphosphate), Sequence Homology, Amino Acid, Protein Folding, DNA, Complementary, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, In Vitro Techniques
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