General

The Prokineticin receptors (PKR₁ and PKR₂) are newly identified G-protein coupled receptors that are activated by a unique pair of ligands [6-8,11]. Prokineticins (PK1 and PK2) are cysteine-rich secreted proteins consisting of 81 and 86 amino acids [4,6,11], and are among the largest known GPCR ligands. Recent studies have revealed that the six N-terminal residues of the prokineticins are essential for activating PKR₁ and PKR₂ [1]. Activation of PKRs leads to mobilization of calcium, phosphoinositide hydrolysis, and activation of PI3 kinase and the mitogen-activated protein kinase (MAPK) pathways [7-8,11]. The involvement of G_i pathways in the receptor signaling transduction, however, is still controversial [4,7-8,11]. While the biology of PKRs is clearly still emerging, published results over the last few years have indicated that PKRs are involved in the regulation of broad functions ranging from angiogenesis, hematopoiesis, neurogenesis, gastrointestinal motility, to circadian rhythms and ingestive behavior [2-6,9-10]. These functions regulated by the PKRs can be classified into two general categories of cell excitability and cell motility, which are consistent with the known signaling transduction mechanisms of PKRs. In a tree of GPCR evolution, PKR₁ and PKR₂ reside between the neuropeptide receptors and the chemokine receptors, which are known to regulate cell excitability and cell motility, respectively. The unusual high conservation between PKR₁ and PKR₂ (85% amino acid identity), despite being on different chromosomes, appears to indicate that these receptors are involved in very crucial processes.

1. Bullock CM, Li JD, Zhou QY. (2004) Structural determinants required for the bioactivities of prokineticins and identification of prokineticin receptor antagonists. Mol Pharmacol, 65 (3): 582-8. [PMID:14978236]

2. Cheng MY, Bullock CM, Li C, Lee AG, Bermak JC, Belluzzi J, Weaver DR, Leslie FM, Zhou QY. (2002) Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature, 417: 405-410. [PMID:12024206]

3. Dorsch M, Qiu Y, Soler D, Frank N, Duong T, Goodearl A, O'Neil S, Lora J, Fraser CC. (2005) PK1/EG-VEGF induces monocyte differentiation and activation. J Leukoc Biol, 78 (2): 426-34. [PMID:15908459]

4. LeCouter J, Kowalski J, Foster J, Hass P, Zhang Z, Dillard-Telm L, Frantz G, Rangell L, DeGuzman L, Keller GA et al.. (2001) Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature, 412 (6850): 877-84. [PMID:11528470]

5. LeCouter J, Zlot C, Tejada M, Peale F, Ferrara N. (2004) Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc Natl Acad Sci USA, 101 (48): 16813-8. [PMID:15548611]

6. Li M, Bullock CM, Knauer DJ, Ehlert FJ, Zhou QY. (2001) Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle. Mol Pharmacol, 59: 692-698. [PMID:11259612]

7. Lin DC, Bullock CM, Ehlert FJ, Chen JL, Tian H, Zhou QY. (2002) Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor. J Biol Chem, 277 (22): 19276-80. [PMID:11886876]

8. Masuda Y, Takatsu Y, Terao Y, Kumano S, Ishibashi Y, Suenaga M, Abe M, Fukusumi S, Watanabe T, Shintani Y et al.. (2002) Isolation and identification of EG-VEGF/prokineticins as cognate ligands for two orphan G-protein-coupled receptors. Biochem Biophys Res Commun, 293 (1): 396-402. [PMID:12054613]

9. Negri L, Lattanzi R, Giannini E, Metere A, Colucci M, Barra D, Kreil G, Melchiorri P. (2002) Nociceptive sensitization by the secretory protein Bv8. Br J Pharmacol, 137 (8): 1147-54. [PMID:12466223]

10. Ng KL, Li JD, Cheng MY, Leslie FM, Lee AG, Zhou QY. (2005) Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling. Science, 308 (5730): 1923-7. [PMID:15976302]

11. Soga T, Matsumoto Si, Oda T, Saito T, Hiyama H, Takasaki J, Kamohara M, Ohishi T, Matsushime H, Furuichi K. (2002) Molecular cloning and characterization of prokineticin receptors. Biochim Biophys Acta, 1579 (2-3): 173-9. [PMID:12427552]